WARNING LETTER
Mark S. Denker, M.D., PA dba Palm Beach Fertility Center
MARCS-CMS 643090 —
November 17, 2022
Delivery Method:
VIA UNITED PARCEL SERVICE
Product:
Biologics
Recipient:
Recipient Name
Mark S. Denker, M.D.
Recipient Title
Owner/Medical Director
Mark S. Denker, M.D., PA dba Palm Beach Fertility Center
7015 Beracasa Way, Suite 201
Boca Raton
,
FL
33433-3453
United States
Issuing Office:
Division of Biological Products Operations I
United States
WARNING LETTER
November 17, 2022
22-643090
Dear Dr. Denker:
The United States Food and Drug Administration (FDA) conducted an inspection of your firm, Mark S. Denker, M.D., PA dba Palm Beach Fertility Center, located at 7015 Beracasa Way, Suite 201, Boca Raton, FL, between May 31 and June 6, 2022. 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 (FDA 483), were presented to and discussed with you at the conclusion of the inspection. The 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)(1)]. For example:
a. Directed semen donor
(b)(6)
answered “yes” to the question, “Have you had sex with another man in the preceding 5 years?” on the
Donor Medical History Interview Form
dated January 22, 2021. The donor was determined “eligible,” and semen was recovered on February 24, 2021.
b. Directed semen donor
(b)(6)
answered “yes” to the question, “Have you lived cumulatively for 5 years or more in Europe from 1980 until the present?” on the
Donor Medical History Interview Form
dated February 3, 2020 and November 4, 2021. The donor was determined “eligible,” and semen was recovered on February 3, 2020, and November 5, 2021.
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)(1)]. Your
Donor Medical History Interview Form
is used as a relevant medical record to determine donor eligibility. However, the questionnaire is inadequate. For example, all donors who were screened using the
Donor Medical History Interview Form
between May 24, 2018, through March 16, 2022 (approximately
(b)(4)
anonymous oocyte donations,
(b)(4)
directed oocyte donations, and
(b)(4)
directed semen donations) were not screened for the following risk factors:
a. Persons who have been treated for or had syphilis within the preceding 12 months.
b. Persons who have tested positive or reactive for West Nile Virus (WNV) infection using an FDA-licensed or investigational WNV NAT screening test in the preceding 120 days.
c. Persons who received any transfusion of blood or blood components in France between 1980 and the present.
d. Your firm’s
Donor Medical History Interview Form
utilized between July 19, 2019 through March 16, 2022 failed to screen for persons who are current or former U.S. military members, civilian military employees, or dependents of a military member or civilian employee who resided at U.S. military bases in Northern Europe (Germany, Belgium, and the Netherlands) for 6 months or more
cumulatively
from 1980 through 1990, or elsewhere in Europe (Greece, Turkey, Spain, Portugal, and Italy) for 6 months or more
cumulatively
from 1980 through 1996.
3) Failure to maintain documentation of the donor eligibility determination, including the name of the responsible person who made the determination and the date of the determination [21 CFR 1271.55(d)(1)(iii)]. For example, a review of records for all donors with recoveries between July 19, 2019 and March 16, 2022 (approximately
(b)(4)
anonymous oocyte donations and
(b)(4)
directed semen donations) found that those records were missing the name of the responsible person who made the donor eligibility determination and the date of the determination.
4) Failure of the summary of records, required under 1271.55(a)(3), to contain a listing and interpretation of the results of all communicable disease tests performed [21 CFR 1271.55(b)(2)]. For example, the test specimen collected from directed semen donor
(b)(6)
on January 29, 2021 was reported as “positive” for “CMV Total Antibody” on February 3, 2021. However, the summary of records for donor MB documents that the donor is negative for “Anti CMV Total Antibodies.” Semen was recovered from this donor on February 3, 2021.
5) 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:
a. Directed semen donor
(b)(6)
was determined ineligible on May 1, 2019. However, the
Donor Eligibility Determination Form
notes that the reasons for ineligibility are “high risk behavior” and “resides in Europe.” However, the
Donor Medical History Interview Form
for donor RP only documents that the donor has a high-risk behavior (sex with another male in the preceding five years). There is no documentation of the donor’s residence in Europe, therefore the reason(s) for ineligibility does not accurately reflect what is in the donor’s records.
b. Directed semen donor
(b)(6)
was determined ineligible for semen recovery on February 3, 2021. However, the summary of records does not state the reason for the determination of ineligibility.
c. Directed semen donor
(b)(6)
was determined ineligible for semen recovery on October 25, 2019. However, the summary of records does not state the reason for the determination of ineligibility.
d. Directed semen donor
(b)(6)
was determined ineligible on May 16, 2019. However, the
Donor Eligibility Determination Form
notes the reason for ineligibility as, “Previous infection (Positive RPR) Pt treated
(b)(6)
.” However, the test specimen collected from donor
(b)(6)
on May 8, 2019, tested reactive for RPR and reactive on a “Syphilis MHA-TP” test, which is a treponemal-based assay (confirmatory test). Therefore, the reason(s) for ineligibility does not accurately reflect that the donor had a current positive test for syphilis.
6) 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” means define, document (in writing or electronically), and implement; then follow, review, and as needed, revise on an ongoing basis [21 CFR 1271.47(a)]. For example, your firm's procedures for testing anonymous and directed donors do not include HIV NAT, HBV NAT, HCV NAT, or West Nile Virus as required communicable disease tests.
7) Failure to establish and maintain a standard operating procedure governing the release of an HCT/P from a donor whose specimen tests reactive for evidence of infection due to cytomegalovirus (CMV) [21 CFR 1271.85(b)(2)]. For example, your procedures do not include how the CMV test results will be communicated to the physician responsible for accepting the HCT/P so that they may rely on the information to make informed decisions about the use of an HCT/P in a particular recipient’s situation.
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 is in compliance with all applicable requirements of the federal regulations. You are responsible for reviewing your firm’s operations as a whole to ensure that you are in compliance with applicable FDA regulatory requirements.
We acknowledge receipt of your letter dated June 24, 2022, which provides a response and corrective actions to FDA’s inspectional observations (FDA 483). We have reviewed the corrective actions outlined in the response and we have determined that the response is inadequate to address our concerns.
A previous inspection of your facility conducted between May 10 and 24, 2018, resulted in the issuance of an Untitled Letter dated November 16, 2018. To date, we have not received a response to the Untitled Letter delivered to your firm on November 27, 2018.
However, in your June 12, 2018 response to the FDA 483, you submitted a corrective action plan that committed to both immediate and preventive corrections such as revisions to procedures and forms, retraining of staff, and a commitment by the Medical Director to review donor records to ensure compliance prior to documenting a donor eligibility determination. Despite that commitment, the current inspection (May 31 through June 6, 2022) documented many of the same violations, indicating that your corrective actions either were 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 the following specific concerns and comments regarding your FDA 483 responses and your firm’s corrective actions.
1) In response to Observation 1, you provided an updated
Donor Medical History Interview Questionnaire
and stated that the missing questions were implemented in response to the March 16, 2022, FDA inspection of your sister facility in Aventura, FL. However, you previously stated in your June 12, 2018, response that your revised screening questionnaire was immediately implemented, yet the same risk factors were missing from your donor history questionnaire during the recent inspection that were missing during the 2018 inspection. Your June 24, 2022, response does not address why this revised screening questionnaire was not implemented as promised.
2) In response to Observation 2, we acknowledge that you have revised your donor eligibility determination form; however, in your June 12, 2018, response, you stated the Medical Director would review all donor records and forms prior to final eligibility determination to ensure compliance. Despite this commitment, you continue to have deficiencies with your donor eligibility records. We are concerned about your ability to implement effective corrective actions to prevent the recurrence of the underlying problem pertaining to your firm’s failure to review all required documents prior to determining donor eligibility.
3) In response to Observation 3, you stated that you updated your donor summary of records form to incorporate the results from the physical exam and medical history interview in determining eligibility and provided training to your staff. However, we note that donor records from the current inspection and the 2018 inspection found documentation that donors answered “yes” to the question regarding having lived cumulatively for 5 years or more in Europe from 1980 until the present, yet the donors were determined eligible. Additionally, your June 12, 2018, response stated you would, “Establish a process and procedure to ensure any donor who answers ‘yes’ to having lived cumulatively for 5 years or more in Europe from 1980 until the present will be deemed ineligible.” We are concerned that this repeat observation shows that your 2018 commitment to review donor records prior to determining donor eligibility has not been effective.
As required under 21 CFR 1271.75(d)(1), you must determine to be 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 Secs. 1271.75(a)(1), (b), or (c). As such, directed semen donors AH and GP should have been determined ineligible. Use of HCT/Ps from an ineligible donor is not prohibited in the case of a directed reproductive donor, provided the HCT/P from the donor is properly labeled with the appropriate warning labels, in accordance with 21 CFR 1271.65(b)(2).
4) In response to Observation 4, you stated that you have revised your summary of records form so that it documents only CMV total antibody to avoid confusion and provide clarity. We recommend that you review your donor records to confirm that semen donors who tested positive for CMV total antibody have these test results accurately reflected on the summary of records. Additionally, you do not have a written procedure that addresses how positive CMV test results will be communicated to the physician responsible for accepting the HCT/P so that they may rely on the information to make informed decisions about the use of an HCT/P in a particular recipient’s situation [21 CFR 1271.85(b)(2).] Refer to item 7 on this letter.
5) In response to Observation 5, you stated that you updated your summary of records form to include the reason for ineligibility. However, this same observation was cited during the 2018 inspection of your establishment, and you committed to having the Medical Director review all records and forms prior to documenting the donor eligibility determination. Your previous corrective actions appear to have been ineffective to prevent recurrence of this deficiency.
6) In response to Observation 6, your June 24, 2022, response states that your firm’s procedures were updated to include HIV NAT, HBV NAT, HCV NAT, and West Nile Virus as required donor screening tests. We note that your June 12, 2018, response also committed to updating your procedures to include this same missing testing requirement. However, our review of the selected pages you submitted with your June 24, 2022, response that document revisions to your
HCT/Ps Procedure Manual
noted that they still do not list HBV NAT as a required test for both anonymous and directed donors.
In addition, our review of the submitted pages from your procedure found that they remain deficient for the reasons set forth below. Please note that this list is not necessarily all-inclusive, and it continues to be your responsibility to ensure that your establishment is in full compliance with 21 CFR Part 1271 at all times.
a. The “Donor Testing” section of your procedure states for anonymous donors that, “A positive test to HBsAg may not make the donor ineligible.” In accordance with 21 CFR 1271.80(d)(1), a donor whose specimen tests reactive on a screening test for a communicable disease agent in accordance with Sec. 1271.85 must be determined to be ineligible. This applies to both anonymous and directed donors.
b. The “Donor Testing” section of your procedure states for directed donors that positive results for the relevant communicable diseases listed, “…would require special labeling of HCT/P.” While special labeling is required for donors with positive testing for relevant communicable disease agents under 21 CFR 1271.65(b)(2), we note that your procedure does not require that directed donors with positive test results for a relevant communicable disease agent be determined ineligible.
c. The “Donor Testing” section of your procedure states for directed donors that “A positive test to HBsAg may not require special labeling.” Under 21 CFR 1271.65(b)(2), you must prominently label with a biohazard legend and the applicable warning statement(s), an HCT/P made available for use from a directed reproductive donor who is determined ineligible due to a reactive screening test for a communicable disease agent, in accordance with Sec. 1271.80(d)(1).
We recommend that you review your firm’s procedures and make the necessary changes to ensure they include all steps that you perform in testing, screening, determining donor eligibility, and complying with all other requirements in accordance with 21 CFR 1271 of Subpart C-Donor Eligibility.
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. 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 HCTPExemptions@fda.hhs.gov.
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 21 CFR 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 Colleen M. Aspinwall, Compliance Officer, U.S. Food & Drug Administration, Office of Biological Products Operations – Division 1 at the email address: Colleen.Aspinwall@fda.hhs.gov. If you should have any questions, please contact Colleen Aspinwall 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
Content current as of:
02/07/2023
Regulated Product(s)
Biologics