Inspections, Compliance, Enforcement, and Criminal Investigations
Advanced Reproductive Laboratory 09-Jan-07
Department of Health and Human Services
Public Health Service
January 9, 2007
RETURN RECEIPT REQUESTED
Sy Q. Le, M.D., President/CEO
Advanced Reproductive Laboratory
7501 Las Colinas Blvd, Suite 200
Irving, TX 75063-7518
Dear Dr. Le:
The Food and Drug Administration (FDA) conducted an inspection of your firm, Advanced Reproductive Laboratory, located in Irving, Texas, from October 11, 2006 through October 18, 2006. During the inspection, the FDA investigators documented deviations from the regulations governing human cells, tissues, and cellular and tissue-based products (HCT/P's) set forth in Title 21, Code of Federal Regulations, Part 1271 (21 CFR 1271), issued under the authority of Section 361 of the Public Health Service Act (42 U.S.C. 264).
At the close of the inspection, FDA issued to you a Form 483, Inspectional Observations that describe a number of deviations. The items of concern include, but are not limited to, the following:
1. Failure to determine as ineligible, a donor whose specimen tested reactive on a screening test for a communicable disease agent [21 CFR 1271.80(d)(1)]. Specifically, anonymous donor, [redacted] (chart #63141) tested reactive on a screening test for the antibody to hepatitis C virus (anti-HCV) on June 1, 2005. Oocytes were retrieved from donor [redacted] on July 30, 2005 and were transferred as embryos to a recipient (chart #64099) on August 4, 2005. The results of confirmatory tests notwithstanding, pursuant to 21 CFR 1271.80(d)(1), an anonymous donor must be determined ineligible for donation once a specimen tests reactive on a screening test for a communicable disease agent in accordance with 21 CFR 1271.85.
2. Failure to test using appropriate FDA-licensed, approved, or cleared donor screening tests, in accordance with the manufacturer's instructions, to adequately and appropriately reduce the risk of transmission of relevant communicable disease agents or diseases [21 CFR 1271.80(c)]. Specifically, both anonymous and directed oocyte donors were tested for relevant communicable disease agents using clinical diagnostic tests instead of FDA-licensed, approved, or cleared donor screening tests. Indeed, the laboratories which do your testing perform only clinical diagnostic. viral marker testing unless the testing sample is labeled as a "donor specimen" and is accompanied by a request from your firm to perform donor screening tests. A review of Viral marker testing reports from these laboratories found that the specimens from your anonymous and directed oocyte donors were not identified as "donor specimens", nor were donor screening tests requested by your firm.
3. Failure to test a specimen from an anonymous or directed donor of reproductive cells or tissue to adequately and appropriately reduce the risk of transmission of relevant communicable disease agents of the genitourinary tract, including Chlamydia trachomatis and Neisseria gonorrhea [21 CFR 1271.85(c)]. Specifically, oocytes were recovered from two donors and were transferred to recipients despite the absence of testing for these two diseases. Oocytes were recovered from anonymous donor [redacted](chart #65348) on July 28, 2005 and were fertilized with semen from the recipient's (chart #64995) spouse. Two embryos were transferred to the recipient on August 2, 2005. Oocytes were also retrieved from directed donor [redacted](chart #66416-D) on September 21, 2006 and were fertilized with semen from the recipient's (chart #63212-R) spouse. Two embryos were transferred to the recipient on September 26, 2006.
4. Failure to collect a donor specimen for testing for relevant communicable diseases within 30 days prior to oocyte recovery, or up to 7 days after recovery [21 CFR 1271.80(b)]. Specifically, specimens from the following eight donors were not collected within the required timeframe:
a. The specimen for donor [redacted](chart #65504) was collected on January 11, 2005; however, oocyte recovery was performed on June 10, 2005.
b. The specimen for donor [redacted](chart #65421-D) was collected on January 7, 2005; however, oocyte recovery was performed on June 22, 2005.
c. The specimen for donor [redacted](chart #65505-D) was collected on January 18, 2005; however, oocyte recovery was performed on June 24, 2005.
d. The specimen for donor [redacted](chart #63141) was collected on May 31, 2005; however, oocyte recovery was performed on July 30, 2005.
e. The specimen for donor [redacted] was collected on May 11, 2006; however, oocyte recovery was performed on June 20, 2006.
f. The specimen for donor [redacted](chart #254 IVF-D) was collected on March 10,2006; however; oocyte recovery was performed on April 25, 2006.
g. The specimen for donor [redacted](chart #66187) was collected on March 13, 2006; however, oocyte recovery was performed on April 28, 2006.
h. The specimen for donor [redacted](chart #66416-D) was collected on July 24, 2006; however, oocyte recovery was performed on September 21, 2006.
5. Failure to establish and maintain procedures for all steps that you perform in testing, screening, determining donor eligibility, and complying with all other requirements of Subpart C "Donor Eligibility" in 21 CFR Part 1271. "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)]. Specifically, in at least eight instances you did not follow your own procedures for determining the eligibility of anonymous donors of reproductive cells or tissue prior to performing oocyte retrieval. Your procedure, "Section IV: Donor Eligibility (subpart C)," requires that a Donor Medical History Interview Form be completed for each donor and filed with the donor's medical records. In addition, your firm's procedure requires that the Responsible Person make all eligibility determinations and document the outcome in the donor's record, after reviewing available donor medical records, the Medical History Interview Form, and the results of the physical assessment. The Donor Medical History Interview Form and/or the Donor Eligibility Determination Form were missing or incomplete for donors [redacted].
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 each requirement of the law and applicable regulations. You are responsible for investigating, determining causes of, and correcting the violations identified by FDA, and for reviewing your operations as a whole to assure yourself that you are in compliance with all regulatory requirements applicable to human reproductive HCT/P's and your firm.
We acknowledge receipt of your letter dated November 14, 2006 that provided a preliminary response to FDA's inspectional observations. We have reviewed the corrective actions outlined in the response and we have determined that the actions are inadequate to address our concerns. Our comments to your response follow and are numbered to correspond to the observations listed on the Form FDA 483:
1. In your response to Observations 1, 3, and 5, you briefly state that your "Donor Infectious Disease Interview Form" has been revised and, since the inspection, has been used to screen all potential donors. Regarding the "HCT/P Procedure Manual" you similarly state that henceforth all donors will be screened according to the manual However, we note that a prior version of the Donor Infectious Disease Interview Form was required as part of your donor screening procedure, but was not consistently used to document donor suitability for anonymous and directed oocyte donors. The proposed corrective action does not provide further assurance that the problem will not recur, nor does it detail your plan to ensure that donor records are complete prior to determining eligibility.
2. In your response to Observation 2, your corrective action for ensuring that future donors are screened for Neisseria gonorrhea and Chlamydia trachomatis is to ensure completion of the "Donor Testing Form" prior to accepting donors. We note that 21 CFR 1271.75(c) and 21 CFR 1271.85(c) state that screening and testing for communicable diseases of the genitourinary tract is required for all donors unless the reproductive cells or tissues are recovered by a method that ensures freedom from contamination by infectious disease organisms that may be present in the genitourinary tract. You did not address how you will ensure that all donors are both screened and tested for communicable diseases of the genitourinary tract to prevent this violation from recurring. In addition, you did not indicate whether you plan to review the donor records that were not reviewed during the FDA inspection, to determine if other donors were not screened as required by the regulations.
3. Your corrective action in response to Observation 4 does not address how you will track donors to ensure that testing for all communicable disease agents, as required by 21 CFR 1271.85(a), will be repeated within 30 days of oocyte recovery, when the initial testing may have occurred months before. In addition, your "Donor Testing Form" states that "all testing was done in a CLIA or equivalent CMS approved laboratory." However, you do not specify that testing is performed using appropriate FDA licensed, approved, or cleared donor screening tests as required by 21 CFR 1271.80(c).
4. We also note that your corrective actions attempt to 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 oocyte retrieval. Please explain what corrective actions you will take in regard to completing eligibility determinations and communicable disease testing for these donors, including re-testing using appropriate FDA licensed, approved, or cleared donor screening tests. In your response to this letter, we also request that you detail any additional corrective actions you have taken, and provide complete documentation to demonstrate that the corrective actions are being appropriately implemented.
You should take prompt action to correct these deviations and to prevent their recurrence. Failure to do so may result in FDA initiating regulatory action without further notice. For example, FDA may take possession of and/or destroy violative HCT/P's, or may issue an order to retain, recall, destroy, or cease manufacture of HCT/P's.
We request that you notify this office in writing, within fifteen (15) working days of the receipt of this letter, of the specific steps you have taken to correct these violations, including examples of any documentation showing that corrections have been achieved. If you cannot complete all the corrections before you respond, please explain the reason for your delay and the date by which each item will be corrected and documented.
Please send your reply to the Food and Drug Administration, Attention: Carolyn A. Pinney, Compliance Officer, at the above letterhead address. If you have any questions regarding any issue in the letter, please contact Carolyn A. Pinney at (214) 253-5220.
Michael A. Chappell
Dallas District Director