| Public Health Service Food and Drug Administration |
Department of Health and Human Services
WARNING LETTER
2011-DET-09
June 14, 2011
VIA UPS
William L. Gentry, MD
Medical Director
Advanced Fertility Group, PC
1222 Professional Boulevard
Evansville, Indiana 47714
Dear Dr. Gentry:
The Food and Drug Administration (FDA) conducted an inspection of your firm, Advanced Fertility Group, located at 1222 Professional Boulevard, Evansville, Indiana from March 28, 2011 through April 13, 2011. During this inspection, the FDA investigators 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, Part 1271 (21 CFR 1271), and issued under the authority of Section 361 of the Public Health Service Act (42 USC 264).
The deviations documented on the Form 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 test a specimen from an anonymous or directed reproductive donor of cells or tissue for evidence of infection due to relevant communicable disease agents [21 CFR 1271.85(a)]. For example, on (b)(6), semen was recovered from directed donor (b)(6) and used to fertilize oocytes from an anonymous donor. On (b)(6), two resulting embryos were transferred to a gestational carrier. Samples for communicable disease testing were collected from directed semen donor (b)(6) on (b)(6) but were not tested for Human Immunodeficiency Virus, types 1 and 2, Hepatitis B virus, Hepatitis C virus, and Treponema pallidum.
2. Failure to collect a donor specimen for testing for relevant communicable diseases at the time of recovery of cells from a semen donor; or up to 7 days before or after recovery [21 CFR 1271.80(b)]. For example, a specimen for relevant communicable disease testing was collected from directed semen donor (b)(6) on (b)(6). Semen was not recovered from the donor until (b)(6). The resulting two embryos were transferred to a gestational carrier on (b)(6).
3. Failure to test a specimen from an anonymous or directed reproductive donor of viable, leukocyte-rich cells or tissue to adequately and appropriately reduce the risk of transmission of relevant cell- associated communicable diseases including Human T-lymphotropic virus, types I and II (HTLV-I/II) and/or cytomegalovirus (CMV) [21 CFR 1271.85(b)]. For example,
a. On (b)(6) semen was recovered from directed donor (b)(6) and used to fertilize oocytes from an anonymous donor. On (b)(6), two resulting embryos were transferred to a gestational carrier. Directed semen donor (b)(6) was not tested for Human T-lymphotropic virus, types I and II (HTLV-I/II).
b. On (b)(6) semen was recovered from directed donor (b)(6) and used to fertilize oocytes from the donor’s partner. On (b)(6), three resulting embryos were transferred to a gestational carrier. Directed donor (b)(6) was not tested for cytomegalovirus (CMV).
4. Failure to test a specimen from an anonymous or directed reproductive donor of cells or tissue to adequately and appropriately reduce the risk of transmission of relevant communicable disease agents of the genitourinary tract [21 CFR 1271.85(c)]. For example, you failed to test for Chlamydia trachomatis and/or Neisseria gonorrhea in the following instances where the HCT/Ps were not recovered by a method that ensures freedom from contamination of the cells or tissue by infectious disease organisms that may be present in the genitourinary tract:
a. On (b)(6) oocytes were recovered from directed oocyte donor (b)(6). Four resulting embryos were transferred to the recipient on (b)(6). Oocyte donor (b)(6) was not tested for Chlamydia trachomatis and Neisseria gonorrhea.
b. On (b)(6) oocytes were recovered from anonymous oocyte donor (b)(6). Two resulting embryos were transferred to the recipient on (b)(6). Oocyte donor (b)(6) was not tested for Chlamydia trachomatis and Neisseria gonorrhea.
c. On (b)(6) oocytes were recovered from anonymous oocyte donor (b)(6). Two resulting embryos were transferred to the recipient on (b)(6). Oocyte donor (b)(6) was not tested for Chlamydia trachomatis and Neisseria gonorrhea.
d. On (b)(6) oocytes were recovered from anonymous oocyte donor (b)(6). Two resulting embryos were transferred to the recipient on (b)(6). Oocyte donor (b)(6) was not tested for Chlamydia trachomatis and Neisseria gonorrhea.
5. Failure to determine whether an HCT/P donor is eligible based on 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)].
a For example, your firm documented that donors were eligible for donation prior to receiving the results of all required testing for relevant communicable diseases.
i. Anonymous oocyte donor (b)(6) was determined to be eligible for donation on July 6, 2010. The relevant communicable disease testing was completed on July 12, 2010. On (b)(6) oocytes were recovered from donor (b)(6) and two resulting embryos were transferred to the recipient on (b)(6).
ii. Anonymous oocyte donor (b)(6) was determined to be eligible for donation on February 15, 2010. The relevant communicable disease testing was completed on March 24, 2010. On (b)(6) oocytes were recovered from donor (b)(6) and two resulting embryos were transferred to the recipient on (b)(6).
iii. Directed oocyte donor (b)(6)3 was determined to be eligible for donation on September 10, 2010. The relevant communicable disease testing was completed on September 15, 2010. On (b)(6) oocytes were recovered from donor (b)(6) and two resulting embryos were transferred to the recipient on (b)(6).
iv. Anonymous oocyte donor (b)(6) was determined to be eligible for donation on July 10, 2010. The relevant communicable disease testing was completed on September 1, 2010. On (b)(6) oocytes were recovered from donor (b)(6) and three resulting embryos were transferred to the recipient on (b)(6).
v. Anonymous oocyte donor (b)(6) was determined to be eligible for donation on April 15, 2010 and May 20, 2010. The relevant communicable disease testing was completed on July 2, 2010. On (b)(6) oocytes were recovered from donor(b)(6) and two resulting embryos were transferred to the recipient on(b)(6).
b. Your firm did not document donor eligibility prior to the retrieval and transfer of HCT/Ps. For example, on (b)(6), semen was recovered from directed donor (b)(6) and used to fertilize oocytes recovered from the donor’s partner, directed donor (b)(6). Three resulting embryos were transferred to a gestational carrier on (b)(6). There was no documentation of donor eligibility determination for either directed oocyte donor (b)(6) or directed semen donor (b)(6).
6. Failure to screen an anonymous or directed reproductive donor of 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)]. For example, records for the following donors did not include documentation of a donor medical history interview, as defined in 21 CFR 1271.3(n), and/or physical examination of a living donor, both required as relevant medical records under 21 CFR 1271.3(s).
a. Directed oocyte donor (b)(6) and directed semen donor (b)(6) answered “yes” to the questions on the Risk Factor Screening record pertaining to residence in, or travel to, several European countries including England. There is no indication on either donor’s form that follow-up questions were asked to determine the length of time spent in those countries in order to rule out their risk of exposure to Creutzfeldt-Jakob disease. On (b)(6) oocytes were recovered from directed oocyte donor (b)(6) and fertilized with semen from directed donor (b)(6). Two resulting embryos were transferred to a gestational carrier on (b)(6).
b. On (b)(6), semen was recovered from directed donor (b)(6) and used to fertilize oocytes from an anonymous donor. On (b)(6) two resulting embryos were transferred to a gestational carrier. There is no evidence in the medical chart that a physical exam was performed or a medical history interview was ever performed for directed semen donor (b)(6).
c. On (b)(6), semen was recovered from directed donor (b)(6) and used to fertilize oocytes from an anonymous donor. Two resulting embryos were transferred to a gestational carrier on (b)(6) The directed donor’s medical chart did not show evidence that there was a physical exam to screen for clinical evidence of communicable diseases.
7. Failure to provide a distinct identification code to accompany the HCT/P at all times, that relates the HCT/P to the donor and to all records pertaining to the HCT/P [21 CFR 1271.55(a)(1)]. For example, the only means of linking a donor with their test results was through an impermanent specimen sample number that was generated for that series of tests. This number appeared on the Test Request form and the Statement of Laboratory Testing Results form, but not on any of the summary documents such as the Donor Eligibility Record. It was also the only identifier on the Statement of Laboratory Testing Results; the donor’s name and/or donor ID number were not included.
The above identified violations 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 all of the FDA regulatory requirements.
We acknowledge receipt of your letter dated April 25, 2011 that provides a response to FDA’s inspectional observations. We have reviewed the corrective actions outlined in the response and we have determined that the response is inadequate to address our concerns. The response outlines changes to your donor testing procedures, including implementation of revised forms and the implementation of a new protocol. These corrective actions may address communicable disease testing and donor eligibility of future donors; however, you did not indicate how you plan to address the failure to determine the eligibility of previously accepted donors for whom communicable disease testing and donor eligibility determinations were not completed prior to transfer of resulting embryos. Please explain what corrective action you will take in regard to completing eligibility determinations and communicable disease testing for these donors.
Also your revised “Procedure to Ensure that no Embryos are Transferred Until all FDA Communicable Disease Screening has been Verified” version 002, effective date April 25, 2011 does not include required testing of the human immunodeficiency virus, type 1 and hepatitis C virus by the nucleic acid test (NAT). This testing is also not included on the form for the “FDA Required Acceptance: Summary of Records,” revised April 20, 2011.
We also note that a completed Justification of Departure from SOP Regarding FDA Established Donor Screening Criteria form was included in the records for a directed donor with incomplete donor testing and/or screening. The form was used to document that screening and/or testing were not completed as required. Under 21 CFR 1271.47(d), “You must record and justify any departure from a procedure relevant to preventing risks of communicable disease transmission at the time of its occurrence. You must not make available for distribution any HCT/P from a donor whose eligibility is determined under such a departure unless a responsible person has determined that the departure does not increase the risks of communicable disease transmission through the use of the HCT/P.” In the Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) (August 27, 2007) [http://www.fda.gov/cber/gdlns/tissdonor.htm], FDA clarifies that a departure from procedures is an “intended change from an established procedure, including a standard operating procedure (SOP), which occurs before the HCT/P is distributed, and is consistent with applicable regulations and standards.” We note that the departure from procedure for your directed donor was not consistent with applicable regulations, which require donor testing in accordance with 21 CFR 1271.80 and 1271.85, and donor screening in accordance with 21 CFR 1271.75 for anonymous and directed reproductive donors of cells or tissue.
You should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the Food and Drug Administration without further notice.
We request that within fifteen (15) working days of receipt of this letter, you notify this office in writing, of the specific steps you have taken to correct the noted deviations, and to prevent their recurrence. If corrective action cannot be completed within fifteen (15) working days, please state the reason for the delay and the time frame within which the corrections will be completed.
Please send your written reply to the Food and Drug Administration, Attention: Catherine V. Quinlan, Compliance Officer, 300 River Place, Suite 5900, Detroit, Michigan 48207. If you have any questions regarding any issues in this letter, please contact Ms. Quinlan at (313)393-8153.
Sincerely,
/S/
Kathleen M. Sinninger
Acting District Director
Detroit District Office
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