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WARNING LETTER

California IVF Fertility Center MARCS-CMS 598552 —

Delivery Method:
VIA UNITED PARCEL SERVICE
Reference #:
OBPO 20-598552
Product:
Biologics
Recipient:
Recipient Name
Ernest J. Zeringue, MD
Recipient Title
President and Medical Director
California IVF Fertility Center

2590 Venture Oaks Way, Ste 103
Sacramento, CA 95833-3200
United States

Issuing Office:
Office of Biological Products Operations - Division II

United States

February 26, 2020

Warning Letter #OBPO 20-598552

Dear Dr. Zeringue:

The United States Food and Drug Administration (FDA) conducted an inspection of your firm, California IVF Fertility Center, located at 2590 Venture Oaks Way, Suite 103, Sacramento, CA, between October 4, 2019 and October 11, 2019. During the inspection, an FDA Investigator 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, 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 test a specimen from an anonymous or directed donor of reproductive cells or tissue, whether viable or non-viable, for evidence of infection due to relevant communicable disease agents [21 CFR 1271.85(a)]. Living HCT/P donors should be tested for West Nile Virus (WNV) using an FDA-licensed Nucleic Acid Test (NAT) donor screening test for HCT/Ps recovered between June 1 and October 31 every year. For example, approximately (b)(4) oocyte donors and (b)(4) semen donors were not tested for WNV during that time period since November 1, 2017.

2) Failure to screen a donor of reproductive cells or tissue by reviewing the donor's relevant medical records for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases [21 CFR 1271.75(a)(l)]. For example, your firm's Donor Infectious Disease Risk Questionnaire (Implemented: 10/2017) is used as a relevant medical record to determine donor eligibility. However, the form does not include screening for all conditions and/or behaviors that increase a donor's relevant communicable disease risk. For example, questions for the following risk factors for relevant communicable disease agents and diseases are missing from your screening forms:

a. Persons who have tested positive or reactive for WNV infection using an FDA-licensed or investigational WKV NAT donor screening test in the preceding 120 days;

b. Persons who received any transfusion of blood or blood components in France between 1980 and the present;

c. Persons who have had a medical diagnosis of ZIKA Virus (ZIKV) in the past 6 months;

d. Persons who resided in, or traveled to, an area with an increased risk for ZIKV transmission within the past 6 months; and

e. Persons who have had sex within the past 6 months with a person with a medical diagnosis of ZIKV in the past 6 months or who resided in an area with an increased risk for ZIKV transmission within the past 6 months.

3) Failure to establish and maintain procedures for all steps performed in testing, screening, and determining donor eligibility, and complying with all other requirements of subpart C "Donor Eligibility" in 21 CFR Part 1271.45-1271.90. "Establish and maintain" mean define, document, and implement; then follow, review, and as needed, revise on an ongoing basis [21 CFR 1271.47(a)]. For example, you have not established a written procedure that includes screening for risk factors related to ZIKV and WNV and testing donors for HIV, HBV, and HCV using NAT.

The deviations identified above are not intended to be an all-inclusive list of deficiencies. It is your responsibility to ensure that your establishment fully complies with the law. You are responsible for reviewing your firm's operations as a whole to assure that you are in compliance with all statutory and regulatory requirements.

We acknowledge receipt of your response dated October 24, 2019 to the Form FDA 483, List of Inspectional Observations and your inquiry dated October 31, 2019 to CBER regarding FDA guidance documents. We have reviewed your response and provide the following comments:

You object to each observation on the basis that FDA's guidance documents contain recommendations, unless specific regulatory or statutory requirements are cited. Indeed, it is FDA's regulation at 21 CFR 1271.3(r) that provides a definition of "relevant communicable disease agent or disease" (RCDAD) and lists specific disease agents identified as RCDADs. FDA regulations also provide a mechanism for designating additional RCDADs in the future, based on the risk of transmission, severity of effects, and development of appropriate screening measures and/or the availability of an appropriate FDA-licensed, approved or cleared screening test for donor specimens. At the time these regulations were promulgated, the agency stated that it would issue guidance that notifies HCT/P establishments when the agency believes additional relevant communicable disease agents or diseases meet the definition in 21 CFR 1271.3(r)(2).

In March 2016, FDA identified ZIKV as a RCDAD, as defined in 21 CFR 1271.3(r)(2). Therefore, review of relevant medical records, as defined in 21 CFR 1271.3(s) and required under 21 CFR 1271.75, must indicate that a donor of an HCT/P is free from risk factors for, or clinical evidence of, ZIKV infection for purposes of determining donor eligibility.

In September 2016, FDA identified WNV as a RCDAD, based on the risk of transmission, severity of effects, and availability of appropriate screening measures. An FDA-licensed donor screening NAT assay for WNV is available and testing is required in accordance with 21 CFR 1271.85(a).

In accordance with 21 CFR 1271.75, you must screen HCT/P donors for risk factors for, and clinical evidence of, RCDADs. In accordance with 21 CFR 1271.80 and 1271.85, you must test HCT/P donors for evidence of infection due to relevant communicable disease agents to adequately and appropriately reduce the risk of transmission of relevant communicable diseases.

We acknowledge your commitment to revise your procedures and donor screening forms to ensure they include an evaluation of all risk factors for, and clinical evidence of, relevant communicable diseases, as required under 21 CFR 1271. These documents will be reviewed during the next inspection of your establishment.

Please note that if you still have oocytes and/or semen in storage from donors whose screening and/or testing was not completed in accordance with 21 CFR Part 1271, FDA considers the donor eligibility determinations to be incomplete for these donors. For example, donors who were not tested for WNV, donors who were screened using a donor history questionnaire that was missing required screening questions, and donors who were not screened for risk factors for ZIKV. Therefore, as required by 21 CFR 1271.60(a), you must keep these HCT/Ps in quarantine.

Should the need arise in the future to remove any of these oocytes or semen from quarantine, either for use in your own establishment or for transport to another establishment, you may request an exemption or alternative from a requirement in subpart C 21 CFR Part 1271, as specified in 21 CFR 1271.155 (additional information can be found at https://www.fda.gov/vaccines-blood-biologics/tissue-tissueproducts/exemptions-and-alternatives). Please note that 21 CFR 1271.155 requires that you provide justification for use of HCT/Ps from these donors, as well as information on how you have mitigated the risk consistent with the goals of protecting the public health and/or preventing the introduction, transmission, or spread of communicable diseases. Before any of these HCT/Ps can be removed from quarantine the request must be granted by FDA.

If you still have embryos in storage for which the donor eligibility requirements under part 1271, Subpart C are not met, please note that FDA considers the donor eligibility determinations to be incomplete for these donors. Therefore, as required by 21 CFR 1271.60(a), you must keep these HCT/Ps in quarantine. Should the need arise in the future to remove any of these HCT/Ps from quarantine, either for use in your own establishment or for transport to another establishment, you may release these HCT/Ps from quarantine (21 CFR 1271.90(b)) provided they are labeled in accordance with the applicable regulations at 21 CFR 1271.90(c).

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 cannot complete all corrections within fifteen (15) working days, please explain the reason for your delay and the time frame within which the remaining corrections will be completed.

Your response should be sent to the following address: U.S. Food and Drug Administration, Sam Labinjo, 550 W. Jackson, Suite 1500, Chicago, IL or emailed to Samuel.Labinjo@fda.hhs.gov. If you should have any questions, please contact Sam Labinjo, Compliance Officer, at (312) 596-4254 or via email.

Sincerely,
/S/
Karlton T. Watson
Program Division Director
Office of Biological Products Operations - Division II

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