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WARNING LETTER

June 24, 2022

22-633890

Dear Dr. Zhang:

The United States Food and Drug Administration (FDA) conducted an inspection of your firm, Zhang Medical P.C. dba New Hope Fertility Center, located at 4 Columbus Circle, 4th Floor, New York, NY, between November 1, 2021 and November 30, 2021. During the inspection, an FDA Investigator documented significant deviations 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 Part 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)]. For example:

  a) Anonymous oocyte donor (b)(6) answered “yes” to residing in or traveling to an area with an increased risk for Zika virus (ZIKV) transmission in the past 6 months and was determined eligible on March 17, 2021.

  b) Anonymous oocyte donor (b)(6) answered “yes” to residing in or traveling to an area with an increased risk for ZIKV transmission in the past 6 months and was determined eligible on July 1, 2020.

  c) Anonymous oocyte donor (b)(6) answered “yes” to having sex with a male in the past 6 months who has been diagnosed with ZIKV or who resided in or traveled to an area with an increased risk for ZIKV transmission in the past 6 months and was determined eligible on May 21, 2020.

2) Failure to determine whether a donor is eligible based upon the results of donor screening in accordance with 21 CFR 1271.75 and donor testing in accordance with 21 CFR 1271.80 and 21 CFR 1271.85 [21 CFR 1271.50(a)]. The eligibility of three anonymous oocyte donors was determined and documented prior to the receipt of the results of donor testing for relevant communicable disease agents. For example:

  a) A specimen for communicable disease testing was collected from anonymous oocyte donor (b)(6) on (b)(6). Donor (b)(6) was determined to be eligible on April 17, 2021, but test results were not reported until April 20, 2021.

  b) A specimen for communicable disease testing was collected from anonymous oocyte donor (b)(6) on (b)(6). Donor (b)(6) was determined to be eligible on January 8, 2021, but test results were not reported until January 9, 2021.

  c) A specimen for communicable disease testing was collected from anonymous oocyte donor (b)(6) on (b)(6). Donor (b)(6) was determined to be eligible on (b)(6), but test results were not reported until March 18, 2019.

3) Failure of a responsible person to determine and document the eligibility of a cell or tissue donor [21 CFR 1271.50(a)]. For example:

a) The records for anonymous oocyte donor (b)(6) did not contain any documentation that the donor was determined “eligible.” The records contained a Repeat Donor Eligibility Determination Summary of Records form for anonymous oocyte donor (b)(6), dated December 5, 2019. However, the record did not document that the donor was determined eligible.

b) The records for directed semen donor (b)(6) (semen recovery date: (b)(6)) did not contain any documentation of the donor eligibility determination, which must be based on the results of mandatory donor screening and testing.

4) 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)(1)]. For example:

a) A review of 111 anonymous oocyte donor cycle records from October 2018 to November 2021, found at least 25 anonymous oocyte donors were missing documentation of responses to one or more questions that ask about risk factors for, and clinical evidence of, relevant communicable disease agents and diseases on your firm’s Donor Medical History Interview Questionnaire (revision: 9/5/2018). For example:

i. Anonymous oocyte donor (b)(6) failed to document answers to questions regarding: (1) persons who have been treated for syphilis, Chlamydia trachomatis or Neisseria gonorrhea in the past 12 months; (2) persons who have traveled to Creutzfeldt-Jakob (CJD) risk countries; and (3) persons who have resided in or traveled to areas with an increased risk for ZIKV transmission within the past 6 months. Despite the missing documentation, donor (b)(6) was determined eligible on April 10, 2021.

ii. Anonymous oocyte donor (b)(6) failed to document answers to questions regarding: (1) persons who have resided in or traveled to areas with an increased risk for ZIKV transmission within the past 6 months; and (2) persons who have had sex with a male who has been diagnosed with ZIKV or resided in or traveled to areas with an increased risk for ZIKV transmission in the past 6 months. Despite the missing documentation, donor (b)(6) was determined eligible on September 9, 2020.

iii. Anonymous oocyte donor (b)(6) failed to document an answer to the question regarding persons who have resided in or traveled to areas with an increased risk for ZIKV transmission in the past 6 months. Despite the missing documentation, donor (b)(6) was determined eligible on September 2, 2020.

iv. Anonymous oocyte donor (b)(6) failed to document answers to questions regarding: (1) persons who have resided in or traveled to areas with an increased risk for ZIKV transmission within the past 6 months; , and (2) persons who have had sex with a male who has been diagnosed with ZIKV or resided in or traveled to areas with an increased risk for ZIKV transmission in the past 6 months. Despite the missing documentation, this donor (b)(6) and was determined eligible on March 25, 2020.

v. Anonymous oocyte donor (b)(6) failed to document an answer to the question regarding persons who have had sex with anyone in the past 12 months who would answer “yes” to questions 1-4 (risk factors for HIV, Hepatitis B and/or Hepatitis C). Despite the missing documentation, donor (b)(6) was determined eligible on March 19, 2020 and May 21, 2020.

vi. Directed oocyte donor (b)(6) failed to document an answer to the question regarding persons who have been in jail for more than 72 consecutive hours in the past 12 months. Despite the missing documentation, donor (b)(6) was determined ineligible on November 24, 2020, for other reasons that were not documented.

b) FDA has identified that ZIKV is a relevant communicable disease agent or disease under 21 CFR 1271.3(r)(2). Therefore, review of relevant medical records, as defined in 21 CFR 1271.3(s), must indicate that a potential donor of HCT/Ps is free from risk factors for, or clinical evidence of, ZIKV infection for the purpose of determining donor eligibility. Your oocyte donor screening for risk factors associated with ZIKV was limited to the countries and areas listed on your Donor Medical History Interview Questionnaire (revision: 9/5/2018). This list of countries was not complete. From October 2018 to November 2021, this questionnaire was used to screen 111 anonymous and 10 directed oocyte donors.

5) Failure to determine as ineligible a donor whose specimen tests reactive on a screening test for a communicable disease agent for which testing is required under 21 CFR 1271.85 [21 CFR 1271.80(d)(1)]. For example, a specimen for communicable disease testing collected on (b)(6), from directed oocyte donor (b)(6), tested reactive on a screening test for the antibody to hepatitis B core antigen (anti-HBc). The donor was not determined ineligible, as required

6) Failure to collect donor specimens for testing for relevant communicable diseases at the time of recovery of the cells or tissue from the donor; or for oocyte donors, within 30 days prior to oocyte recovery or up to seven days after recovery [21 CFR 1271.80(b)]. For example, a specimen for communicable disease testing was collected from directed oocyte donor (b)(6), on (b)(6). However, the oocytes were recovered from the donor on (b)(6).

7) Failure to include in the summary of records a statement noting the reason(s) for the determination of ineligibility in the case of an HCT/P from a donor who is ineligible based on screening and released under 21 CFR 1271.65(b) [21 CFR 1271.55(b)(4)]. For example, the following directed oocyte donors were determined ineligible without documentation noting the reason(s) for ineligibility:

a) Directed oocyte donor (b)(6) was determined ineligible on February 2, 2021 (oocyte recovery date: (b)(6)).
b) Directed oocyte donor (b)(6) was determined ineligible on November 24, 2020 (oocyte recovery date: (b)(6)).
c) Directed oocyte donor (b)(6) was determined ineligible on October 31, 2020 (oocyte recovery date: (b)(6)).
d) Directed oocyte donor (b)(6) was determined ineligible on August 11, 2020 (oocyte recovery date: (b)(6)).
e) Directed oocyte donor (b)(6) was determined ineligible on January 4, 2020 (oocyte recovery date: (b)(6)).

The deviations identified above are not intended to be an all-inclusive list of deficiencies at your facility. You are responsible for reviewing your firm’s operations as a whole to ensure that you are in compliance with all applicable FDA regulatory requirements.

We acknowledge receipt of your letter dated December 10, 2021, which responds to the Form FDA 483 and describes various corrective actions. We have reviewed the corrective actions outlined in the response, and we have determined that they are inadequate to address our concerns. A previous inspection of your facility conducted in August-September 2014 resulted in a Warning Letter, dated November 20, 2014, and a Regulatory Meeting held on March 18, 2015. Thereafter, you submitted a corrective action plan and committed to monitoring its effectiveness on a long-term basis. Despite that commitment, which included retraining of staff, implementation of a new checklist for donor screening, and revisions to your procedures, the current inspection (November 1-30, 2021) documented many of the same violations, indicating that your corrective actions were either not implemented or were not effective to prevent the recurrence of the previously identified violations. The Agency continues to have serious concerns about your establishment’s ability to maintain compliance with 21 CFR Part 1271.

Additionally, we have specific concerns and comments about your response to observation 4, regarding labeling of HCT/Ps for which the applicable donor eligibility requirements were not met. You submitted a copy of your new procedure, SOP: FDA Tissue Labeling Policy (SOP# N001, Revision 1, implementation date: December 2021), which included labeling scenarios based on the status/designation of each gamete donor. We are concerned that the scenarios do not meet all of the donor eligibility requirements under 21 CFR Part 1271. For example:

1) Case #2 (page 2) states that “...Sexually Intimate Partners who use their own gametes with the intention to use a third-party and, have elected to undergo all the FDA testing/screening requirements and are found to be “ELIGIBLE,” will be labeled as below:

OOCYTE SEXUALLY INTIMATE PARTNER DETERMINED ELIGIBLE
SEMEN SEXUALLY INTIMATE PARTNER DETERMINED ELIGIBLE.”

Please note that sexually-intimate partners (SIPs), who donate gametes with the intention to use a third-party (gestational carrier) are considered directed donors and MUST have a complete donor screening, donor testing, and donor eligibility determination, as required under 21 CFR 1271.50. In addition, the labeling for such HCT/Ps should not designate the donors as SIPs.

2) Case #4 (page 3) states, “Sexually intimate partner determined to be ELIGIBLE and oocyte donor NOT EVALUATED then tissue status form will be labeled as below:

SEMEN SEXUALLY INTIMATE PARTNER DETERMINED ELIGIBLE
OOCYTE DONOR NOT TESTED

EMBRYOS “NOT EVALUATED FOR INFECTIOUS SUBSTANCES”
“WARNING: Advise recipient of communicable disease risks.’”

Your procedure does not explain under which circumstances an oocyte donor would be allowed to be untested and the HCT/Ps labeled with such warning statements. As a reminder, all anonymous or directed donors are required to have a complete donor screening, donor testing, and donor eligibility determination under 21 CFR 1271.50.

3) Case #7 (page 4) describes labeling for HCT/Ps for which the oocyte donor is also the recipient and has not been screened and tested. The procedure notes that the HCT/Ps will be labeled with the statement, “OOCYTE SEXUALLY INTIMATE PARTNER NOT TESTED.” We note that this labeling statement would be inaccurate for this scenario, as an oocyte donor who is also the recipient is an autologous donor. Please review your procedure to ensure the appropriate labeling statements in 21 CFR 1271.90(c) are included.

4) Case #8 (page 4) also appears to describe labeling for HCT/Ps for which the oocyte donor is also the recipient. Please review your procedure to ensure the appropriate labeling statements in 21 CFR 1271.90(c) are included.

Finally, during our review of your Donor Medical History Interview Questionnaire (revision: 9/5/2018), we noted that question #25b states, “Within the past 6 months, have you had sex with a male who has been diagnosed with the Zika Virus or lived in …?” The question should ask, “Within the past 6 months, have you had sex with a person who has been diagnosed with the Zika Virus or lived in …”

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, this includes donors who failed to answer all screening questions on your donor history interview questionnaire and donors who were not appropriately screened for ZIKV risk factors. 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 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: Exemptions and Alternatives | FDA.The email address for submissions is [email protected].

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. 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 email addresses: Valerie Grecek-Trinh, Compliance Officer; email address: [email protected] and Colleen Aspinwall, Compliance Officer; email address: [email protected]. If you should have any questions, please contact Valerie Grecek-Trinh, Compliance Officer at (904) 353-4560 ext. 118 or Colleen Aspinwall, Compliance Officer at (561) 416-1065 ext. 1105 or via e-mail.

Sincerely,
/S/

Michael W. Roosevelt
Program Division Director
Office of Biological Products Operations – Division 1