Inspections, Compliance, Enforcement, and Criminal Investigations
Advanced Reproductive Laboratory Response Letter
January 27, 2007
Food and Drug Administration
Attention: Carolyn A. Pinney, Compliance Officer
4040 North Central Expressway
Dallas, TX 75204-3145
Re: Letter 2007-DAL-WL-4
Dear Ms. Pinney:
We have received your letter dated January 9, 2007 and wish to outline in detail the steps we have taken to address your concerns. First, however, we respectfully disagree with your conclusion that anonymous donor [redacted] (chart #63141) was not an acceptable donor. We will review with you the laboratory results in chronological order:
1. [redacted] had first donated oocytes in January 2002. Her first STD screening panel, therefore, dates back to December 2001. It was completely negative including Hepatitis C Antibody status of non-reactive.
3. Upon STD screening May 31, 2005, her Hepatitis C Antibody screen came back as "Reactive". All of her liver function testing was normal. We initially told her that she would not be able to donate and that she should consult her primary care physician (PCP) for further management. The patient was in a stable monogamous marriage and she had no risk factors for contraction of Hepatitis C upon questioning.
4. In order to validate the result of the initial screening, her PCP ran a series of confirmatory tests on June 2, 2005 that included:
Hepatitis C RNA, PCR Qualitative Screen---Negative
Hepatitis C RNA, PCR Quantitative <50 IU/ml
Hepatitis C Antibody Negative
5. Even though all of her confirmatory tests came back negative, we ran another Hepatitis C Antibody Screen on June 8, 2005 and this was also negative.
6. Another STD screen was performed on July 5, 2005 to conform with the requirement of having a negative STD panel within 30 days of oocyte collection. This panel again demonstrated that her Hepatitis C Antibody screen was negative. The oocyte retrieval was performed on July 30, 2005.
All of the referenced laboratory results are being included with this letter (Appendix I). Given the fact that she had three negative Hepatitis C Antibody screens (including negative results by PCR for both qualitative and quantitative testing) after the "positive" one, we conclude that a laboratory error (false positive) had occurred. We feel that we adequately proved the donor to be safe to use. In addition, the recipient couple and their gestational carrier were fully informed of the above results and agreed to proceed forward (documentation has also been provided for this consent).
We will now address your concerns numbered 1-4 as outlined on pages 4 and 5 of the Warning Letter regarding implementation of corrective actions.
l. Although we have had the HCT/P Procedure Manual in place since May 2005, we were slow in learning how to integrate the new FDA requirements into our traditional donor screening process. As the results, several versions of the screening forms were used at different times for different donors. Since the site visit in October 2006, however, we have streamlined and implemented a structured and mandatory series of visits (both nurse and doctor), each with its appropriate form(s), all of which the donor must pass before being accepted to be a donor. The forms are included (Appendix II) for your review. We have outlined the screening steps as below:
A. Initial Interview-Our donor screening process begins with an intensive, detailed meeting with the Authorized Clinical Person (a designated nurse or a physician). This visit entails asking a series of questions from the Infectious Disease Screening Interview (Form 1) designed to elicit any high-risk behavior or potential exposure to infectious agents. Once the Authorized Clinical Person determines that the donor has passed this form, he (she) then signs and dates the form and the donor may proceed on to the next step.
B. Initial STD Screen- The results are recorded in the Donor Testing Data (Form 2). If the donor has donated within the prior 12 months, then laboratory work at our center or at another fertility center will be used for the "Initial STD Screen". If this is the donor's first time, then the indicated labs will be drawn as well as GC and Chlamydia screen and a urine drug screen. Any positive screen test will be confirmed with more specific tests (to rule out a false positive). Any validated positive result from the Initial STD Screen will make the donor ineligible. Once the donor has passed her Initial STD Screen she may proceed on to the visit with the physician.
C. Evaluation by the Physician-The physician will first review Forms 1 and 2 to check for accuracy. After the history is taken, the physician will then perform a detailed physical examination and enter the findings in the Donor Physical Assessment Form (Form 3). The physician will then either "accept" or "reject" the donor by marking the appropriate box and will sign and date the form. Only after a potential donor has been accepted by a physician will she be allowed to proceed forward. She will then have a "Final STD Screen" approximately 7 days prior to the start of stimulation medications (and within 30 days prior to oocyte retrieval) and the results are recorded in Form 2. Any validated positive test at this point will make the donor ineligible.
D. Final Approval-This step is performed by the Responsible Person (a physician) who will review the previous 3 forms. The final determination is recorded in the Egg Donor Eligibility Determination (Form 4) and must be signed and dated by the Responsible Person prior to the initiation of HMGs (Human Menopausal Gonadotropins) which are used to stimulate the donor's ovaries.
2. In response to Observation 2, we have determined that all donors will be screened for GC/Chlamydia at the initial screen and again within 7 days of HMG start. Our IVF nurse in charge of the donor/recipient cycles will review any charts that were not reviewed during the FDA inspection to determine if other donors were not screened according to regulations. Any inappropriately screened donor found will be contacted and offered free repeat STD screening if she did not have similar screening subsequent to the retrieval date.
3. In response to Observation 4, we shall refer you again to the previously mentioned forms (1-4). As you will notice on Form 2 (Donor Testing Data), the STD screening is divided into "Initial STD Screen" and "Final STD Screen". Next to each of these is a blank for the date to specify the exact day that the samples were taken. The Final STD Screen is to be drawn approximately 7 days prior to the start of HMGs. Once these results are known and determined to be negative, then the Responsible Person (a physician) will complete Form 4 (Egg Donor Eligibility Determination). The Responsible Person must sign and date Form 4 prior to the initiation of ovarian stimulation in the donor. This ultimately places the responsibility for verifying the status of the "Final STD Screen" with the Responsible Person.
Regarding the use of FDA licensed or approved donor screening tests, we have reached an agreement with [redacted]. We will send the collected samples to [redacted] facility (directed by [redacted], M.D.) who will, in turn, forward these samples to a designated FDA-approved branch to run the actual tests. In addition, [redacted] has recently created a FDA Panel (Female)-code #[redacted] which includes Hep C Core Total Ab, RPR, Hep B Surface Antigen, Hep C Virus Antibody, and HIV-1/HIV-2 Antibody Screen. This panel, along with GC/Chlamydia cultures will constitute our "Initial and Final STD Screens". We have included the curriculum vitae, Texas license number, CLIA certification, and CAP certification for Dr. [redacted] and her laboratory for your perusal (Appendix III).
4. For the last concern (#4 on page 5) you want us to address our plan of action to prevent any future donors from being used without properly timed screening. As a group, our physicians and nurses have studied the charts which were flagged by the FDA in an effort to improve the safety of future cycles. We have reviewed our new mandatory, step-wise protocol with our nursing staff so that any omissions will be caught prior to the initiation of HMGs in the donors. In addition, employees who are involved with the donor cycles will be evaluated periodically on their understanding of the HCT/P process and remedial training will be provided for those who did not pass the competency checklist.
As an example of our implementation of the HCT/P guidelines, we have included with this letter the evaluation of a recent anonymous egg donor (Appendix IV). Donor [redacted] (MR# Donor-014) had her initial STD screen on 11/21/06 which she passed. The screening interview (Form 1) and physical assessment (Form 3) were completed on 12/13/06. Her final STD screen was completed on 1/02/07 which she also passed. Final approval for her to donate eggs was given on 1/03/07 (Form 4). Ovarian stimulation was initiated on 1/06/07 and her eggs were retrieved on 1/18/07.
With regards to the donors who did not have STD screenings in compliance with FDA regulations we will contact them to offer retesting free of charge. For those who have since donated eggs elsewhere, we will ask them to release copies of the test results to be included in the chart.
We wish to proceed with full compliance with all federal regulations and will respond immediately to any requests or suggestions for further actions or remedial efforts. We will continue to follow policies and procedures implemented according to the FDA's guidelines.
If possible, we would like this letter to be added to the Response Section of our warning letter posted on the FDA website. Thank you for your attention to this matter.
Sy Q Le, MD
Medical Director, CEO
Advanced Reproductive Laboratory, LP
Advanced Reproductive Care Center, PA
Cc: Mr. Michael A Chappell