- Delivery Method:
- VIA UNITED PARCEL SERVICE
Fady Sharara, MD
- Virginia Center for Reproductive Medicine
11150 Sunset Hills Road, Suite 100
Reston, VA 20190-5321
- Issuing Office:
- Division of Biological Products Operations I
555 Winderley Place, Suite 200
Mainland, FL 32751
VIA UNITED PARCEL SERVICE
Warning Letter #OBPO 19-007
July 1, 2019
Fady Sharara, MD
Virginia Center for Reproductive Medicine
11150 Sunset Hills Road, Suite 100
Reston, VA 20190-5321
Dear Dr. Sharara:
The United States Food and Drug Administration (FDA) conducted an inspection of your firm, Virginia Center for Reproductive Medicine, located at 11150 Sunset Hills Road, Suite 100, Reston, VA, from February 13, 2019 through February 25, 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. The items of concern include, but are not limited to, the following:
1. Failure to test a specimen from an anonymous or directed reproductive donor of cells and tissue, whether viable or non-viable, for evidence of infection due to relevant communicable disease agents [21 CFR 1271.85(a)]. Testing for relevant communicable diseases, including HIV-1/2, hepatitis B, hepatitis C, syphilis, gonorrhea, and chlamydia, was not performed for the following anonymous oocyte donors. For example:
- Anonymous oocyte donor (b)(4) was determined eligible on February 5, 2019, however there was no record listing the test results for all required relevant communicable disease testing.
- Anonymous oocyte donor 261 was determined eligible following donor screening and a physical examination on February 5, 2019, however there was no record listing the test results for all required relevant communicable disease testing.
- Anonymous oocyte donor (b)(4) was determined eligible following donor screening and a physical examination on February 8, 2019. Although a sample for donor testing was collected on February 8, 2019, the testing was performed using test kits that were not FDA-licensed, approved, or cleared donor screening tests.
- Anonymous oocyte donor (b)(4) was determined eligible following donor screening and a physical examination on February 6, 2019. Although a sample for donor testing was collected on February 6, 2019, the testing was performed using test kits that were not FDA-licensed, approved, or cleared donor screening tests.
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, your questionnaire does not include screening for all conditions and/or behaviors that increase a donor’s relevant communicable disease risk. For example, the following questions are missing from your questionnaire:
- Persons who have been treated for or had syphilis within the preceding 12 months.
- Persons who have received any transfusion of blood or blood components in France between 1980 and the present.
- Persons who have tested positive or reactive for West Nile Virus (WNV) infection using an FDA-licensed or investigational WNV NAT donor screening test in the preceding 120 days.
- Persons who have had a medical diagnosis of Zika virus (ZIKV) in the past 6 months.
- Persons who have had sex within the past 6 months with a person who resided in, or traveled to, an area with an increased risk for ZIKV transmission within the past 6 months.
3. 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), (b), or (c) [21 CFR 1271.75(d)]. For example:
- Directed semen donors (b)(4) answered “yes” on the Donor Medical History Interview Form to the question, “(Men only) Have you had sex with another man in the preceding five years?” These donors were determined eligible on January 27, 2017, January 27, 2017, April 2, 2018, October 5, 2017, October 5, 2017, and August 28, 2017, respectively.
- Directed semen donors (b)(4) answered “yes” on the Donor Medical History Interview Form to the questions, “Have you lived cumulatively for 5 years or more in Europe from 1980 until the present?” and/or “Have you spent three months or more cumulatively in the UK from the beginning of 1980 through the end of 1996?” Donors (b)(4) were determined eligible on January 27, 2017, and donor (b)(4) was determined eligible on May 16, 2017 and December 25, 2018.
- Directed semen donor (b)(4) answered “yes” on the Donor Medical History Interview Form to the question, “Have you resided in, or traveled to, an area with active ZIKV transmission within the past 6 months?” Donor (b)(4) was determined eligible on May 16, 2017 and December 25, 2018.
- Directed semen donor (b)(4) answered “yes” on the Donor Medical History Interview Form to the question, “Have you been diagnosed with or treated for Chlamydia?” There was no documentation of when the diagnosis was or evidence that treatment was more than 12 months prior. Donor (b)(4) was determined eligible on October 5, 2017.
4. Failure of a responsible person to determine and document the eligibility of a donor of reproductive cells or tissue based on the results of donor screening and testing [21 CFR 1271.50(a)]. For example:
- The records for directed semen donor (b)(4) did not contain any documentation that the donor was determined “eligible.” There is no record documenting the donor eligibility determination for directed donor HV (semen recovery date: May 8, 2018), which must be based on the results of donor screening and testing.
- Oocytes were recovered from anonymous donor (b)(4) on January 18, 2019. Although the responsible person signed and dated the Donor Eligibility Determination Form, the record did not document that the donor was determined eligible.
5. Failure to determine whether a donor is eligible based upon the results of donor screening in accordance with 1271.75 and donor testing in accordance with 1271.80 and 1271.85 [(21 CFR 1271.50(a)]. For example:
- Semen was recovered from directed donor (b)(4) on November 13, 2018. However, there was no documentation of a physical examination.
- Semen was recovered from directed donor (b)(4) on November 13, 2018. However, there was no documentation of a physical examination.
6. Failure to provide a summary of records to accompany an HCT/P, that contains a listing and interpretation of the results of all communicable disease tests performed [21 CFR 1271.55(b)(2)]. For example, the summary of records currently in use does not list testing for West Nile Virus (WNV).
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 federal regulations. You are responsible for reviewing your operations as a whole to assure you are in compliance with FDA’s regulatory requirements.
We acknowledge receipt of your letter dated March 4, 2019, 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 they are inadequate to address our concerns. A previous inspection of your facility conducted during May-June 2013 resulted in a Warning Letter dated September 10, 2013. Despite your commitment to correct the previously noted violations, the current inspection (February 13-25, 2019) 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.
Additionally, we have the following specific concerns and comments regarding your responses and your firm’s corrective actions, as follows:
1. In response to Observation 1, we acknowledge the revisions to your Donor Medical History Interview Form submitted with your response, however our review of the form noted that multiple questions on the form are still incorrect or missing, as follows:
- Question #9 states, “Have you had a tattoo, ear piercing, or body piercing in the last 12 months in which sterile procedures were shared?” The question should ask if such activities were performed in which sterile procedures were not used.
- Question #13 regarding a medical diagnosis or suspicion of West Nile Virus (WNV) infection states, "If the answer is yes to this question defer donation for 28 days from onset of symptoms…." However, persons who have had a medical diagnosis or suspicion of WNV infection should be deferred for 120 days following diagnosis or onset of illness, whichever is later. (See section IV.E of the HCT/P Donor Eligibility Determination Guidance).
- Question #26 regarding risks of variant Creutzfeldt-Jakob Disease (vCJD) for persons who lived on military bases in Northern Europe for 6 months or more “continuously” from 1980 through 1990 or elsewhere in Europe for 6 months or more “continuously” from 1980 through 1996. Use of the word “continuously” is not correct. The question should ask if persons lived 6 months or more cumulatively in those areas.
- Question #28 has not been revised accordingly. The question should ask, “Have you received any transfusion of blood or blood components in the U.K. or France between 1980 and the present?”
- Question #31 does not adequately assess a donor's residence in, or travel to, areas with active ZIKV transmission, according to the Centers for Disease Control and Prevention (CDC). The areas listed on the form do not include all international ZIKV risk areas identified by the CDC, nor do they include the areas in the U.S. that are at risk for ZIKV. Additionally, the three items listed as risk factors for ZIKV do not adequately evaluate a donor’s risk for ZIKV, as there is no place for a donor to record a “yes” or “no” answer to the questions.
2. In response to Observation 2, you stated that the HCT/Ps recovered from directed semen donors who answered “yes” to a high-risk behavior question would be labeled as “ineligible.” However, you did not address your failure to determine the donors ineligible at the time of donation, nor did you address the additional questions that were answered “yes,” such as a risk of vCJD due to residence in Europe, residence/travel to an area with active ZIKV transmission, or having been diagnosed or treated for Chlamydia. We note that this same issue was cited in your 2013 Warning Letter and your response to that letter stated that you had corrected the violations.
3. Your response to Observation 3 did not include the specific steps your firm has taken to prevent the recurrence of the underlying problem pertaining to your firm’s failure to review all required documents prior to determining donor eligibility. We note that this violation was also cited in the 2013 Warning Letter and you stated, “We have instituted all the above checks and double checks to make sure that deficiencies such as the ones noted by the FDA inspector will not occur.”
4. In response to Observation 4, regarding (b)(4) who were determined to be eligible despite not being tested for any relevant communicable disease agents, you stated, “These were clearly a mistake as nothing was yet done for these potential donors.” We note that under 21 CFR 1271.50(a), a donor eligibility determination must be made based on the results of a complete donor screening and complete donor testing. (b)(4) were determined to be eligible in February 2019 without any results of testing in their donor records. This practice is not in compliance with 21 CFR 1271 and the donor eligibility determinations for these donors are incomplete.
5. In response to Observation 5, you stated, “We agree that this was completely missed but when discovered the donor was retested. This was the only ‘miss’ that we had and we have taken corrective measures to ensure that testing is done (b)(4).” We note that the donor referenced in this observation was a directed semen donor, not an oocyte donor. In addition, while you stated that the donor was re-tested (on January 10, 2019) once the error was discovered, you documented the donor to be eligible on December 25, 2018 based on the results of testing from the sample collected on December 21, 2018. This was not within (b)(4) of retrieval, which occurred on January 10, 2019.
6. In response to Observation 6, we acknowledge that you have revised specific sections of your HCT/Ps Procedure Manual (v. 2.00), but we continue to have concerns with your revisions as well as additional sections of your procedures manual. Your procedures remain deficient for the reasons set forth below. Please note that this list is not necessarily all-inclusive. It continues to be your responsibility to ensure full compliance with 21 CFR Part 1271.
- In the section titled “Zika infection,” risk factor #3 should match the language used on your Donor History Interview Form. The question should read, “Sex within the past 6 months with a person….” instead of “Sex within the past 6 months with a male….”
- In the section titled, “CJD or vCJD infection,” the second bulleted item from the bottom states, “received any transfusion of blood or blood components in the U.K. between 1980 and the present.” That risk factor has still has not been corrected to include France.
- The procedure has not been corrected to include the requirement to determine as ineligible a donor who has been treated for or had Chlamydia trachomatis within the preceding 12 months.
- The “Donor Screening” section of your procedure manual, under “Directed Donor,” lists high-risk behaviors and conditions to look for during review of a donor’s relevant medical records. The procedure states for infection with HIV, hepatitis, syphilis, vaccinia, sepsis, HTLV, and CJD/vCJD that, “A finding of any of the following would require special labeling of HCT/P.” While special labeling is required for directed reproductive donors with such conditions, you must also determine a potential donor to be ineligible when donor screening indicates risk factors for, or clinical evidence of, any of the relevant communicable disease agents or diseases for which screening is required [21 CFR 1271.75(d)(1)].
- The "Donor Testing" section of your procedure manual 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.
- The "Donor Testing" section of your procedure manual 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 such donors 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 as noted above.
- The "Donor Testing" section of your procedure manual 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 the appropriate 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. 1271.85 (ie: HBsAg).
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 of subpart C - Donor Eligibility.
7. In response to Observation 8, you provided an updated Donor Testing Form and you stated, “The new summary of records now includes ‘NAT’ for HIV, HCV, HBV, and/or WNV.” Our review of this form found that it still does not include testing results for WNV. In addition, we note that the form has been updated to include test results for “HIV, type 1, NAT” and “HIV, type 2, NAT.” We note that there are currently no FDA-licensed, approved, or cleared nucleic acid tests (NAT) for donor screening for HIV-2.
We continue to be concerned about your ability to implement effective corrective actions. Your September 19, 2013 response to the Warning Letter regarding this same issue included a revised VCRM Donor Summary of Records form. That form contained the required information under 21 CFR 1271.55(b), including the designations of “eligible” or “ineligible” for documenting donor eligibility determinations, which is consistent with the language in 21 CFR 1271.50. However, our review of the (b)(4) donor records collected during the most recent inspection found that none of the records included the updated summary of records form that was part of your corrective actions in 2013.
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 the regulations at 21 CFR Part 1271, FDA considers the donor eligibility determinations to be incomplete for these donors. For example, donors who were not tested for relevant communicable disease agents, 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 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: http://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/RegulationofTissues/ExemptionsandAlternativeProcedures/default.htm). Please note that the 21 CFR 1271.155 regulation 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.
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, such as an Order to Cease Manufacturing of HCT/Ps.
We request that you respond in writing within fifteen (15) working days from the date you receive this letter of 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. In addition, due to our concerns with your inability to implement effective corrective actions, we request that you meet with FDA to discuss your firm’s lack of compliance with the regulations. Please contact the FDA representative below to make arrangement for a meeting.
Your response should be sent to the following address: U.S. Food and Drug Administration, Cherlita Honeycutt, 6000 Metro Drive, Suite 101, Baltimore, Maryland 21215 or emailed to Cherlita.Honeycutt@fda.hhs.gov. If you should have any questions, please contact Cherlita Honeycutt, Compliance Officer, at (410) 779-5412 or via email.
Program Division Director
Office of Biological Products Operations – Division 1