• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

  • Print
  • Share
  • E-mail

Order to Cease Manufacturing of HCT/Ps - New York Fertility Institute

PDF Printer Version (PDF - 89KB)

March 1, 2013

HAND DELIVERED

Majid Fateh, M.D.
Medical Director
New York Fertility Institute
1016 5th Avenue
New York, NY 10028

Dear Dr. Fateh:

Your firm, New York Fertility Institute (or Establishment), located at 1016 5th Avenue, New York, New York, 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 August 23 and September 5, 2012, and at the conclusion of the inspection, the FDA investigator issued to Dr. Khalid M. Sultan, IVF Director, a Form FDA-483, Inspectional Observations.  Our review of the information and records examined and collected during the inspection revealed significant violations by New York Fertility Institute 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. 

Therefore, pursuant to 21 CFR 1271.440(a)(3), you1 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 with 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 are 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 samuel.barone@fda.hhs.gov.

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:

DONOR ELIGIBILITY

  1. Failure to determine as ineligible a donor whose specimen tests reactive on a screening test for a communicable disease agent in accordance with 1271.85 [21 CFR 1271.80(d)(1)].  For example:
    1. The specimen from anonymous oocyte donor -b(6)-, collected on March 12, 2010, tested positive on a screening test for the antibody to Hepatitis B core antigen.  Donor -b(6)- was determined eligible on March 20, 2010.  Twenty-two oocytes were recovered from donor -b(6)-on March 24, 2010.  
       
    2. The specimens from anonymous oocyte donor -b(6)-, collected on December 29, 2008, November 5, 2009, December 30, 2009, June 21, 2011, and June 29, 2011, tested positive on a screening test for the antibody to Hepatitis C virus.

      1. Ten oocytes were recovered from donor -b(6)-on July 5, 2011.
         
      2. Twenty-one oocytes were recovered from donor -b(6)-on January 11, 2010. 
         
      3. Twenty-three oocytes were recovered from donor -b(6)-on November 16, 2009. 
         
      4. Thirty-two oocytes were recovered from donor -b(6)-on January 12, 2009. 
         
  2. Failure to use appropriate FDA-licensed, approved, or cleared screening tests to test a specimen from an anonymous or directed reproductive donor of cells and tissue for evidence of infection due to relevant communicable disease agents [21 CFR 1271.80(c) and 21 CFR 1271.85(a)]. Despite the missing test results, these donors were determined eligible.
    1. Nineteen anonymous oocyte donors did not have their specimens tested for human immunodeficiency virus, type 1 (HIV-1) and hepatitis C virus (HCV) by the ---b(4)-------------------------
       
    2. There is no record that donor -b(6)-was tested for HIV-1, human immunodeficiency virus, type 2 (HIV-2), hepatitis B virus, HCV, and Treponema pallidum at the time of oocyte recovery on December 31, 2010.
       
    3. The donor specimen collected from anonymous oocyte donor -b(6)-on December 30, 2009 was not tested for HIV-1 and HIV-2.
       
  3. 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.  The reproductive cells or tissue 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)].  Sixteen anonymous oocyte donors’ specimens were not tested for Chlamydia trachomatis and Neisseria gonorrhea at the time of each donation.  Despite the missing test results, these donors were determined eligible. 
     
  4. 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)(1)].  Human transmissible spongiform encephalopathy, including variant Creutzfeldt-Jakob disease (vCJD), and HIV are relevant communicable diseases under 21 CFR 1271.75(a)(1).  Donor --b(6)-- responses on six separate donor history questionnaires indicate a risk factor for human transmissible spongiform encephalopathy, including vCJD.  Specifically, Donor   ---b(6)-- answered “yes” to the health history question, “Have you lived cumulatively for 5 years or more in Europe from 1980 until the present?” on six separate donor history questionnaires.  In addition, the donor’s responses indicate a potential risk factor for HIV.  Specifically, the donor answered “yes” to the question, “Have you been with a man who has had sex with another man in the past 5 years?” on four separate donor history questionnaires.  This would be considered a risk factor for HIV if the donor’s sexual contact with the person had occurred within the preceding 12 months.  There was no documentation to show that you obtained from the donor information concerning whether the sexual contact occurred within the preceding 12 months.  Despite the risk factor for human transmissible spongiform encephalopathy and potential risk factor for HIV, donor -b(6)-was determined eligible and oocytes were recovered from the donor on November 18, 2009, March 19, 2010, and November 1, 2010. 
     
  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)]. Specifically, the eligibility of the following oocyte donors was determined and documented prior to receipt of the results of donor testing for relevant communicable disease agents.  For example:
    1. The specimens for communicable disease testing were collected from anonymous donor  -b(6)-on December 2 and 5, 2011, and the results were reported on December 7 and 8, 2011. Donor -b(6)-was determined eligible on December 2, 2011.
       
    2. The specimen for communicable disease testing was collected from anonymous donor     -b(6)- on January 28, 2011, and the results were reported on January 31, 2011. Donor       -b(6)-was determined eligible on January 28, 2011.
       
    3. The specimen for communicable disease testing was collected from anonymous donor     -b(6)-on December 17, 2010, and the results were reported on December 19 and 21, 2010. Donor -b(6)-was determined eligible on December 17, 2010.
       
  6. Failure to collect donor specimens for testing for relevant communicable diseases at the time of recovery of the cells or tissue from the donor; or for oocyte donors, within 30 days prior to oocyte recovery or up to seven days after recovery [21 CFR 1271.80(b)].  For example:
    1. The specimen from anonymous oocyte donor -b(6)- was collected on September 29, 2011; however 8 oocytes were recovered from donor -b(6)- on November 9, 2011. 
       
    2. The specimen, for Chlamydia trachomatis and Neisseria gonorrhea testing, from anonymous oocyte donor -b(6)- was collected on June 21, 2010; however 21 oocytes were recovered from donor -b(6)-on August 23, 2010. 
       
    3. The specimen from anonymous oocyte donor -b(6)- was collected on January 21, 2010; however 12 oocytes were recovered from donor -b(6)-on February 24, 2010.
       
  7. Failure to maintain records that are accurate, indelible, and legible [21 CFR 1271.55(d)(2)]. For example, a review of your anonymous oocyte donor records found that the "Donor Eligibility Determination Signature Forms," used to document donor eligibility, did not have documentation of the donor name or donor number in order to relate the record to a specific donor.  

     
  8. 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)].  Under 21 CFR 1271.75(a), you must screen a 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 1271.3(s) defines the term “relevant medical records” to include a current report of the physical examination of a living donor.  For example, your records for the following 49 donations from a total of 12 anonymous oocyte donors lack documentation of your review of a current report of the physical examination of the donor.  For each of these donations, the most recent physical examination of the donor had occurred more than six months before the date(s) of oocyte recovery.2

Donor #

Date(s) of Oocyte Recovery Without Documentation of a Current Physical Examination of the Donor

-b(6)-

6/3/09; 9/21/09; 3/1/10; 3/24/10; 5/24/10; 10/8/10; 5/20/11; 11/28/11, 1/23/12

-b(6)-

3/6/06; 3/22/06; 6/26/06; 8/23/06; 10/25/06; 1/5/07; 3/5/07; 7/16/08; 10/17/08; 1/12/09; 9/18/09; 11/18/09; 3/19/10; 11/1/10

-b(6)-

2/21/11

-b(6)-

8/20/12

-b(6)-

1/9/12

-b(6)-

6/16/10

-b(6)-

9/1/10; 12/31/10; 3/11/11; 4/4/11; 4/21/12

-b(6)-

11/16/09; 1/11/10; 7/5/11

-b(6)-

2/17/12; 4/11/12

-b(6)-

7/29/09; 11/2/09; 2/19/10; 6/16/10; 10/11/10

-b(6)-

2/15/10

-b(6)-

8/24/07; 1/18/08; 9/8/08; 3/16/09; 5/13/09; 2/3/10

  1. 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)].  For example, your standard operating procedure, "Section IV: Donor Eligibility (subpart C)" fails to include the requirement that repeat anonymous donors undergo a complete donor screening procedure, including a physical examination, at least every six months in order to be eligible for an abbreviated donor screening procedure under 21 CFR 1271.75(e).  Instead, the procedure only states that “Repeat donors must undergo full testing at least every 6 months." 

On September 14, 2012, FDA received your written response, dated September 12, 2012, to the Form FDA-483, List of Inspectional Observations, issued to New York Fertility Institute at the close of the inspection.  We have reviewed the corrective actions outlined in the response and we have determined that they are inadequate.  You stated that the inspectional observations “will be addressed appropriately and proper procedures and protocols instituted so as to bring the practice into full compliance with FDA regulations.”  However, your response to several of the inspectional observations demonstrates a lack of understanding of the applicable regulatory requirements.  Additionally, your response addresses only prospective changes to your practices and does not address the inadequacy of donor screening and relevant communicable disease testing for previous HCT/P donors.  You did not discuss plans to review previous donor records to determine whether additional violations exist, nor did you address the increased risk of communicable disease transmission for HCT/Ps remaining in storage at your firm.  

We also have specific comments regarding your response, as follows:

  1. In your response to Observation 1, you indicated that you relied on the FDA guidance document titled “Nucleic Acid Testing (NAT) for Human Immunodeficiency Virus Type 1 (HIV-1) and Hepatitis C Virus (HCV): Testing, Product Disposition, and Donor Deferral and Reentry” (available at: http://www.fda.gov/downloads/biologicsblood%20vaccines/guidancecomplianceregulatoryinformation/guidances/blood/ucm210270.pdf) to determine whether certain tests are required for donors of reproductive HCT/Ps.  However, that guidance document is inapplicable because it addresses blood donors, not donors of HCT/Ps.  The requirements for testing HCT/P donors to adequately and appropriately reduce the risk of transmission of relevant communicable diseases are found in 21 CFR 1271.80 and 1271.85.  Under 21 CFR 1271.80(c), an establishment must 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.  In the FDA guidance document titled “Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)” (August 27, 2007) (available at: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/
    CellularandGeneTherapy/ucm072929.htm
    ) FDA identifies which FDA-licensed, approved, or cleared donor screening tests are considered adequate and appropriate for detecting the relevant communicable disease agents or diseases under 21 CFR 1271.80(c).  As explained in that guidance, FDA considers the use of HIV-1 NAT and HCV NAT donor screening tests, in addition to serological donor screening tests, to be adequate and appropriate for detecting HIV type 1 infection and Hepatitis C infection.
     
  2. In your response to Observation 2, you stated that your policy on testing for Chlamydia trachomatis and Neisseria gonorrhea was based on the ---b(4)-----------------------------------------------------------------------------------------------------------------------------------------.  However, FDA regulations in 21 CFR 1271.80 require that you test HCT/P donors for the communicable disease agents specified in 21 CFR 1271.85 (including Chlamydia trachomatis and Neisseria gonorrhea for donors of reproductive cells or tissue) at the time of recovery of the cells or tissue (or up to 30 days before or seven days after for oocyte donors).  This requirement applies to anonymous and directed oocyte donors, including repeat donors.  

    Your response to Observation 2 also stated that the “FDA Guidance Manual” allows oocyte donors to be exempt from testing for Chlamydia trachomatis and Neisseria gonorrhea when the oocytes are retrieved in a way that ensures freedom from contamination with these disease agents.  You indicated that your oocyte retrieval methods are based on ----b(4)------------------------------------------------------------- and that you presumed this technique ensured freedom of the oocytes from contamination.  Under 21 CFR 1271.85(c), if the donor’s reproductive cells or tissues are 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, then testing for Chlamydia trachomatis and Neisseria gonorrhea is not required.  However, we note that your records for 19 anonymous oocyte donors contained the form, “Operative Report In Vitro Fertilization (IVF),” which documents the oocyte retrieval procedure.  This form states, “…the patient was taken to the operating room and prepared in the usual manner for a      ----b(4)--------------------------------------------------------------------------------------------------------------------------- ---the method of oocyte recovery documented in your records--does not ensure freedom from contamination of the oocytes by infectious disease organisms that may be present in the genitourinary tract. 
     
  3. In your response to Observation 3, you stated, “The cycle mentioned in the observations had a positive result which was discussed by the Medical Team and a follow up investigation pointed to a false result reporting by the reference laboratory…;” and “The donor (-b(6)-) has been tested at other cycles of donation after the false positive result and found negative for Hepatitis B-core antibody.  The case was discussed at a Medical Team meeting and corrective action taken documented (copy of a letter from Reference laboratory and Medical Team meeting minutes and a subsequent negative donor test result are enclosed).” (emphasis in original).  However, under 21 CFR 1271.80(d)(1), the donor should have been determined ineligible after testing positive for the hepatitis B core antibody (anti-HBc), regardless of the reason for the positive testing.  21 CFR 1271.80(d)(1) requires an establishment to determine as ineligible a donor whose specimen tests reactive on a screening test for a communicable disease agent, in accordance with 21 CFR 1271.85, except for a donor whose specimen tests reactive on a non-treponemal screening test for syphilis and negative on a specific treponemal confirmatory test.  The regulations in 21 CFR Part 1271 do not allow the use of HCT/Ps from an ineligible anonymous donor, nor do they allow subsequent negative testing to qualify or re-qualify a donor who has tested reactive on a screening test for a communicable disease agent. 

    We also note that in the August 24, 2012 letter from your testing laboratory regarding the positive testing for anti-HBc for donor -b(6)-, the laboratory indicated that an investigation into the positive testing could not be conducted due to the amount of time that had passed.  The laboratory stated, “We cannot be sure of the exact reason for the discrepancy observed at that time.” 
     
  4. In your response to Observation 5.c., you stated “the general policy is a donor deferral until the high risk question has been properly investigated by the Medical Team and its potential risk to transmission of communicable disease evaluated.  Following the evaluation, the eligibility determination outcome will be determined.”  Similarly, in your response to Observation 6.a., you stated, “Donor -b(6)-had negative results for HIV and other communicable diseases.  Effective immediately, we have instituted a policy whereby all “yes” answers to high risk questions will be re-evaluated and further investigated by the Medical Team that will make the relevant eligibility decision.”  As described above in item 4 of this Order, in accordance with 21 CFR 1271.75(d)(1), you must determine as ineligible a donor who has 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).  The regulations do not allow your Medical Team to determine that an anonymous donor is eligible if a risk factor for, or clinical evidence of, a relevant communicable disease agent or disease is present. 

This letter confirms the telephone conversation on March 1, 2013, in which notice was given that, pursuant to 21 CFR 1271.440(a)(3), you 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; and
     
  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.

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.  FDA retains authority to pursue other actions and remedies.

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.

Sincerely,

 

Karen Midthun, M.D.
Director, Center for Biologics Evaluation and Research

Effective Date: ___________________________ Time: ________________________

           

Attachments (2)
21 CFR Part 1271
21 CFR Part 16

 


 

Footnotes

1 Throughout this order, “you” refers both to the Establishment, and/or you personally, as well as in your capacity as Medical Director, as appropriate.

2 Under 21 CFR 1271.75(e), an abbreviated donor screening procedure may be used on repeat donations from a living donor if the establishment has performed a complete donor screening procedure, including a physical examination, within the previous six months.