ORDER TO CEASE MANUFACTURING of HCT/Ps -Center for Reproductive Medicine
September 7, 2012
Stephen W. Welden, M.D.
Owner / Medical Director
Stephen W. Welden, M.D, PA dba Center for Reproductive Medicine
18944 N. Dale Mabry Hwy, Suite 101
Lutz, Florida 33548
Dear Dr. Welden:
Your firm, Stephen W. Welden, M.D., PA dba Center for Reproductive Medicine (Center for Reproductive Medicine or Establishment), located at 18944 N. Dale Mabry Hwy, Suite 101, Lutz, Florida 33548, performs donor screening, is responsible for donor testing and determines the eligibility of anonymous and directed donors of reproductive human cells, tissues and cellular and tissue-based products (HCT/Ps), and is therefore a manufacturer of HCT/Ps as defined at 21 CFR 1271.3(d). Your firm also performs other manufacturing steps, such as storage. The Food and Drug Administration (FDA or agency) conducted an inspection of your Establishment between March 2-26, 2012, and at the conclusion of the inspection, the FDA investigator issued you a Form FDA- 483, Inspectional Observations. Our review of the information and records examined and collected during the inspection revealed significant violations by the Center for Reproductive Medicine of Title 21, Code of Federal Regulations, Part 1271 (21 CFR 1271) issued under the authority of Section 361 of the Public Health Service Act (PHS Act) [42 United States Code (USC) 264]. The agency has determined that because your Establishment is in violation of 21 CFR Part 1271, your Establishment does not provide adequate protections against the risks of communicable disease transmission through the use of these HCT/Ps. The agency has also determined that there are reasonable grounds to believe these violative HCT/Ps pose a danger to health, and, accordingly, this Order to Cease Manufacturing is effective immediately. This Order to Cease Manufacturing relates to conduct occurring on or after May 25, 2005, the effective date of the applicable regulations and applies only to HCT/Ps from anonymous and directed donors. A donor eligibility determination is not required for reproductive cells or tissue donated by a sexually intimate partner of the recipient for reproductive use. FDA retains authority to pursue other actions and remedies.
Therefore, pursuant to 21 CFR 1271.440(a)(3), both you individually, and the Center for Reproductive Medicine must:
1. Immediately cease all manufacturing of HCT/Ps from directed or anonymous reproductive tissue donors until compliance with the regulations in 21 CFR 1271 has been achieved and you have been provided written authorization from FDA to resume operations. Under 21 CFR 1271.3(e) manufacture means, but is not limited to, any or all steps in the recovery, processing, storage, labeling, packaging, or distribution of any HCT/P, and the screening or testing of the HCT/P donor;
2. Continue to store all HCT/Ps recovered on or after May 25, 2005, which are in your possession or received after the date of this Order.
Additionally, we request that you immediately notify, by copy of this Order, persons who since May 25, 2005:
- were recipients of anonymous or directed donations of reproductive tissues (such as gestational carriers or surrogates)
- have offspring as the result of an Assisted Reproductive Technology (ART) cycle with your firm, involving an anonymous or directed reproductive tissue donor; or
- have stored tissues that involve anonymous or directed reproductive tissue donors.
We further request that you provide FDA with a copy of the cover letter, if any, you include with the copy of the Order and a list of the individuals you notify.
If you have any clients who, at the time of receipt of this Order, are currently undergoing hormonal stimulation for recovery or implantation of reproductive tissues, please contact Samuel Barone, MD at 301-827-6040 or firstname.lastname@example.org
FDA’s inspection and record review noted significant noncompliance with the federal regulations in areas of your Establishment's operations including, but not limited to, the following:
1. Failure to use appropriate FDA-licensed, approved, or cleared screening tests to test a specimen from the donor of cells and tissues for evidence of infection due to relevant communicable disease agents in order to adequately and appropriately reduce the risk of transmission of relevant communicable diseases [21 CFR 1271.80(c) and 1271.85(a)]. For example:
a. Eleven oocyte donors and two semen donors were not tested for human immunodeficiency virus types 1 (HIV-1) and 2 (HIV-2), hepatitis B and hepatitis C virus (HCV), and Treponema pallidum.
b. Nineteen oocyte donors and two semen donors did not have their specimens tested by nucleic acid testing (NAT) for HIV-1 and HCV.
c. At the time of oocyte recovery, three donors were not tested for HIV-2; one donor was not tested for HIV-2 and Treponema pallidum; and one donor was not tested for anti-HBc.
2. Failure to test a specimen from the donor of viable, leukocyte-rich cells or tissue to adequately and appropriately reduce the risk of transmission of relevant cell associated communicable diseases [21 CFR 1271.85(b)]. Two semen donors were not tested for Human T-lymphotropic virus, types I and II (HTLV-I/II) and/or cytomegalovirus (CMV).
3. Failure to test specimens from donors of reproductive cells or tissue to adequately and appropriately reduce the risk of transmission of relevant communicable disease agents of the genitourinary tract. The reproductive cells or tissues were not recovered by a method that ensured freedom from contamination of the cells or tissue by infectious disease organisms that may be present in the genitourinary tract. [21 CFR 1271.85(c)]. Eighteen oocyte donors and three semen donors were not tested for Chlamydia trachomatis and Neisseria gonorrhea.
4. Failure to collect donor specimens for testing for relevant communicable diseases at the time of recovery of cells or tissue from the donor; or for oocyte donors, within 30 days prior to oocyte recovery or up to seven days after recovery; or for semen donors, up to seven days before or after recovery. [21 CFR 1271.80(b)].
a. Specimens for HIV-1, HIV-2, hepatitis B and C virus, and Treponema pallidum testing for 14 oocyte donors were not collected at the time of recovery or 30 days prior to, or up to seven days after recovery.
b. Specimens for Chlamydia trachomatis and Neisseria gonorrhea testing for 13 oocyte donors were not collected at the time of recovery or 30 days prior to or up to seven days after recovery.
c. Specimens for HIV-1, HIV-2, hepatitis B and C virus, Treponema pallidum, HTLV I/II, CMV, Chlamydia trachomatis, and Neisseria gonorrhea testing for a semen donor were not collected at the time of recovery or seven days prior to, or up to seven days after recovery.
5. Failure to screen an anonymous or directed 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)]. Specifically, records for 29 oocyte donors and three semen donors did not include documentation of your review of the donor’s relevant medical records which includes a donor medical history interview, as defined in 21 CFR 1271.3(n), and physical examination of a living donor (both required as relevant medical records under 21 CFR 1271.3(s)). As a result, there was no documentation of the required screening related to risk factors for the relevant communicable disease agents.
6. Failure of a responsible person to determine and document the eligibility of a cell or tissue donor [21 CFR 1271.50(a)]. Specifically, there was no documentation to show that a responsible person determined that the oocytes and semen donors were eligible based on the results of donor screening and testing.
7. Failure to establish and maintain procedures for all steps performed in testing, screening, 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, and implement; then follow, review, and as needed, revise on an ongoing basis [21 CFR 1271.47(a)]. Specifically, your firm failed to establish and maintain any written procedures to address the steps required for donor screening and determining the donor eligibility of oocyte and semen donors.
8. Failure to establish and maintain a standard operating procedure governing the release of an HCT/P from a donor whose specimen tests reactive for cytomegalovirus (CMV) [21 CFR 1271.85(b)(2)]. “Establish and maintain” means define, document, and implement; then follow, review, and as needed, revise on an ongoing basis [21 CFR 1271.47(a)]. Specifically, your firm failed to establish and maintain a written standard operating procedure regarding the release of semen from donors whose specimens test reactive for CMV. On July 14, 2009, your firm was notified that semen donor (b)(6). tested positive for CMV. The positive result was not noted in the donor’s records and the donor's semen was collected on ---(b)(6)--- and ---(b)(6)-----, and in both instances, later released.
9. Failure to have a distinct identification code affixed to the HCT/P container that relates the HCT/P to the donor and to all records pertaining to the HCT/P [21 CFR 1271.55(a)(1)]. Specifically, your firm labels the embryo containers with the last name of the female owner of the embryo; an untraceable identification code (IVF number); the status/stage of the embryo and the date it was frozen. The IVF number is only used for cryopreservation purposes and because it is not in your firm’s computerized medical records, does not directly link the embryo to the source of the semen and oocytes. Misidentification and mix-up of embryos could result if your firm cryopreserved embryos from two people with the same last name on the same day.
On April 19, 2012, FDA received your written response dated March 29, 2012 to the FDA-Form-483, List of Inspectional Observations, issued to Stephen W. Welden, M.D, PA dba Center for Reproductive Medicine at the close of the inspection. We reviewed the corrective actions outlined in the response and have determined that they are inadequate. You agree that your donor eligibility practices are not in compliance with the applicable regulations in 21 CFR Part 1271 and promise to make corrective actions. However, your response is vague and fails to describe concrete steps you will take to ensure that donor screening, donor testing, donor eligibility documentation and records keeping comply with FDA’s regulations. You failed to provide specific details regarding many of the proposed corrective actions, or a definite timeline for effecting the necessary changes.
This letter confirms the telephone conversation on September 7, 2012, in which notice was given that, pursuant to 21 CFR 1271.440(a)(3), both you individually and Stephen W. Welden, M.D, PA dba Center for Reproductive Medicine must:
1. Immediately cease all manufacturing until compliance with the regulations in 21 CFR 1271 has been achieved and you have been provided written authorization from FDA to resume operations. Under 21 CFR 1271.3(e) manufacture means, but is not limited to, any or all steps in the recovery, processing, storage, labeling, packaging, or distribution of any HCT/P, and the screening or testing of the HCT/P donor;
2. Continue to store all HCT/Ps recovered on or after May 25, 2005, which are in your possession, or received after the date of this Order.
Instructions were given at that time of the telephone conversation to cease manufacturing of HCT/Ps and to continue to maintain existing HCT/Ps in storage, as noted above. Neither you, nor your Establishment, can resume operations without prior written authorization from FDA. Before FDA will issue such an authorization, you must ensure compliance with FDA’s regulations in 21 CFR Part 1271 – including, but not limited to, the Donor Eligibility requirements in 21 CFR 1271, Subpart C. Any continued manufacturing of HCT/Ps in violation of this order constitutes a violation of Section 368 of the PHS Act [42 USC 271], for which criminal penalties may be imposed.
Within five (5) working days from the receipt of this Order to Cease Manufacturing, you may request a hearing on the matter in accordance with 21 CFR Part 16 (copy attached), to Mary A. Malarkey, Director, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research, 1401 Rockville Pike, HFM-600, Rockville, MD 20852 (telephone: 301.827.6190). Should you need additional time in which to request a hearing, please notify us immediately, in writing, of your request for additional time.
Failure to request a hearing within the specified time period constitutes a waiver of the right to a hearing. You may also wish to inform yourself with respect to the agency’s guidelines regarding electronic media coverage of its administrative proceedings, which can be found at 21 CFR 10, Subpart C.
Karen Midthun, M.D.
Director, Center for Biologics Evaluation and Research