Inspections, Compliance, Enforcement, and Criminal Investigations
Manhattan Reproductive Medicine, PC 11/20/13
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
New York District
158-15 Liberty Avenue
Jamaica, New York 11433
November 20, 2013
WARNING LETTER NYK 2014-8
VIA UNITED PARCEL SERVICE
Dr. Hanna Jesionowska
Manhattan Reproductive Medicine, PC
159 E 74th Street, Suite C
New York, NY 10021-3235
Dear Dr. Jesionowska:
The U.S. Food and Drug Administration (FDA) conducted an inspection of your firm, Manhattan Reproductive Medicine, located at 159 E 74th Street, Suite C, New York, NY, from July 26 through July 31, 2013. During this inspection, the FDA investigator 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 (21 USC 264).
The deviations documented on the Form FDA 483, Inspectional Observations, 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 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, a specimen collected from anonymous oocyte donor (b)(4) on May 14, 2012 tested positive for Chlamydia trachomatis (CT). According to your testing laboratory, a second specimen was submitted for testing on May 23, 2012 and also tested positive for CT. A third specimen, also tested on May 23, 2012, tested negative for CT. Despite the repeat positive test results, the donor was determined to be eligible on May 24, 2012, and oocytes were recovered from donor (b)(4) on May 26, 2012.
2. Failure to test a specimen from an anonymous or directed reproductive donor of cells and tissue, whether viable or non-viable, for evidence of infection due to relevant communicable disease agents [21 CFR 1271.85(a)].
For example, there is no documented evidence that anonymous oocyte donor (b)(4) was tested for total antibody to Hepatitis B core antigen (anti-HBc) (specimen collection date January 26, 2012). However, this donor was determined to be eligible on February 1, 2012 and oocytes were recovered from donor (b)(4) on February 6, 2012.
3. 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)(1)].
The regulation at 21 CFR 1271.3(n) defines the donor medical history interview as a documented dialog about a donor's medical history and relevant social behavior, including activities, behaviors, and descriptions considered to increase the donor's relevant communicable disease risk. A review of your anonymous oocyte donor records from January 2010 to July 2013 found that the responses to the donor medical history questions regarding risk factors of communicable disease agents were not documented or maintained. However, these donors were determined to be eligible by the Medical Director and were allowed to donate. For example there is no documentation of the responses to the donor medical history questions for the following anonymous oocyte donors:
a. Donor (b)(4) donated oocytes on seven occasions for 11 recipients between February 18, 2011 and May 8, 2013.
b. Donor (b)(4) donated oocytes on seven occasions for 13 recipients between November 21, 2011 and May 17, 2013.
c. Donor (b)(4) donated oocytes on April 18, 2013 for one recipient.
d. Donor (b)(4) donated oocytes on eight occasions for 15 recipients between November 21, 2011 and May 17, 2013.
e. Donor(b)(4) donated oocytes on December 17, 2012 for two recipients.
f. Donor (b)(4) donated oocytes on two occasions for three recipients between April 2, 2011 and February 6, 2012.
g. Donor (b)(4) donated oocytes on six occasions for nine recipients between March 7, 2011 and September 11, 2012.
h. Donor (b)(4) donated oocytes on two occasions for three recipients between August 31, 2011 and July 25, 2012.
4. Failure to test a donor for relevant communicable diseases 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)].
Your establishment uses a contract testing laboratory to test donor specimens for relevant communicable diseases. You failed to ensure that the laboratory responsible for testing donor specimens utilizes FDA-licensed, approved, or cleared donor screening tests for Human Immunodeficiency Virus (HIV types 1 and 2), anti-HBc and Hepatitis C virus. For example, specimens collected from anonymous oocyte donor (b)(4) on September 19, 2011 and January 9, 2012 and anonymous oocyte donor (b)(4) on October 31, 2011 were tested for Hepatitis C virus using a test method that is not approved for screening HCT/P donors. The specimen test reports dated September 23, 2011 and January 14, 2012 for donor (b)(4) and November 5, 2011 for (b)(4) state that, "This assay should not be used for blood donor screening, associated re-entry protocols, or for screening Human Cell, Tissues and Cellular Tissue-Based Products (HCT/P)." Anonymous donor (b)(4) was determined eligible on September 23, 2011 and January 14, 2012 and oocytes were recovered from the donor on September 29, 2011 and January 17, 2012 Anonymous donor (b)(4) was determined eligible on November 5, 2011 and oocytes were recovered from the donor on November 12, 2011.
5. Failure of a responsible person to determine and document the eligibility of a donor of reproductive cells or tissue based on the results of donor screening and testing [21 CFR 1271.50(a)].
For example, the eligibility of anonymous oocyte donors was sometimes determined and documented prior to your firm receiving the results of testing for relevant communicable disease(s). The following oocyte donors were determined to be eligible before receipt of the results of testing:
a. Anonymous oocyte donor (b)(4) was determined eligible on June 10, 2011, however, the final result of HIV testing for this donor was not reported by the testing lab until June 14,2011.
b. Anonymous oocyte donor (b)(4) was determined eligible on October 25, 2012, however, the results of HIV-1/2; hepatitis B; hepatitis C and RPR testing for this donor were not reported by the testing lab until November 7, 2012.
6. Failure to affix a distinct identification code to the HCT/P container, e.g., alphanumeric, that relates the HCT/P to the donor and to all records pertaining to the HCT/P and, except in the case of autologous donations, directed reproductive donations, or donations made by first degree or second-degree blood relatives, does not include an individual's name, social security number, or medical record number [21 CFR 1271.55(a)(1)]. On several occasions, the anonymous donor identification codes were not accurately documented on the test result reports received from the laboratory. The error was not detected and corrected by your staff. For example, donor (b)(4) was identified as (b)(4) on the test result form dated October 1, 2010; donor (b)(4) was identified as (b)(4) (September 20, 2011); and donor (b)(4) was identified as (b)(4) (April 4, 2011).
The deviations identified above 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 the federal regulations. You are responsible for reviewing your firm's operations as a whole to assure that you are in compliance with all of the FDA regulatory requirements.
We acknowledge receipt of your letter dated August 20, 2013 that provides a response to FDA's Inspectional Observations (Form FDA 483). We have reviewed the corrective actions outlined in the response and we have determined that the response does not adequately address our concerns. We are also concerned that you did not convey in your response that you are making a reasonable attempt to correct the noted violations and do not accept responsibility for the deficiencies. Your response to several of the inspectional observations cited in the FDA-483 also demonstrates a Jack of understanding of the applicable regulatory requirements.
We have specific comments regarding your response,as follows:
1. In your response to FDA 483 Observation 1, you provided a letter from your testing lab that stated the donor tested positive for Chlamydia trachomatis twice within nine days and a negative result was obtained only after the test was performed a third time. Your standard operating procedure entitled "Section IV: Donor Eligibility (subpart C)" section "Oocyte Donors" states, "Chlamydia -Chlamydia trachomatis -A positive result would make the donor ineligible." This requirement is in accordance with 21 CFR 1271.80(d), which requires you to determine a donor to be ineligible if their specimen tests reactive on a screening test for a communicable disease agent in accordance with Sec. 1271.85. However, donor (b)(4) was determined eligible and was allowed to donate.
2. FDA 483 Observation 2(a) states that there was no evidence that donor (b)(4) was tested for the antibody to Hepatitis B core antigen (anti-HBc), yet the donor was determined to be eligible to donate oocytes. You responded that the donor was "tested for Hepatitis B with HBsAg on 1/26/12 and it was negative." These are actually two separate and required tests for the Hepatitis B virus. Under 21 CFR 1271.85(a) and 1271.80(c), you are required to adequately and appropriately reduce the risk of transmission of relevant communicable diseases by testing donors for evidence of infection due to relevant communicable disease agents, including the Hepatitis B virus. FDA considers the FDA-licensed screening test for Hepatitis B surface antigen (HBsAg) and the FDA-licensed screening test for the total antibody to Hepatitis B core antigen (anti-HBc), collectively, to be appropriate FDA licensed donor screening tests for evidence of infection due to Hepatitis B virus. The HBsAg test closely follows the course of infection and is used to detect donors who are potentially infectious; the anti-HBc test is an indicator of current or previous infection with Hepatitis B. (See section VI.A of 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) ("HCT/P Donor Eligibility Determination Guidance").
3. None of the donors listed in FDA 483 Observation 2(c) had a documented medical history interview with the results of donor screening and therefore no proof of their eligibility to donate. We acknowledge that your form, "Questionnaire: High Risk Group Evaluation" will be utilized to document answers to donor screening questions in the future. We remind you that any changes to your firm's operations must be included in your procedures. In addition, while your response addresses the use of the new form to document donor screening questions for prospective donors, you did not discuss plans to re-screen previous oocyte donors whose screening was not documented to determine whether additional violations exist.
4. Although your contract lab is licensed, CLIA-certified and registered with the FDA as an HCT/P establishment, for some tests performed, they did not test your donors using FDA licensed, approved, or cleared donor screening tests (FDA483 Observation 3). Your response did not address plans to contact these donors for re-testing using FDA-licensed, approved, or cleared donor screening tests.
5. A donor's eligibility to donate cannot be established before all results of communicable disease testing are received and reviewed (FDA 483 Observation 4). Anonymous oocyte donor (b)(4) was determined to be eligible on June 10, 2011, however; the final result of HIV testing for this donor was not reported by the reference lab until June 14, 2011. Anonymous oocyte donor (b)(4) was determined to be eligible October 25, 2012. Your response states that the preliminary negative results for this donor were faxed by your testing lab on October 23, 2012. However, our review of the testing report you provided with your response includes only the results for HTLV-I/II testing. The results of HIV-1/2, hepatitis B, hepatitis C, and RPR testing for this donor were not reported by the testing lab until November 7, 2012, as documented on the additional testing report you provided with your response.
6. Regarding your response to FDA 483 Observation 5, we remind you that any changes to your firm's operations and procedures must also include re-training of your personnel to ensure compliance with 21 CFR 1271.
You should take prompt action to correct these deviations and prevent their recurrence. Failure to do so may result in FDA initiating regulatory action without further notice.
We request that you respond in writing within fifteen (15) working days from your receipt of this letter, outlining the specific steps you have taken or plan to take to correct these violations and prevent their recurrence. If you cannot complete all corrections within 15 working days, please explain the reason for your delay and the timeframe within which the remaining corrections will be completed.
Please send your written response to:
Patricia A. Clark, Compliance Officer
U.S. Food and Drug Administration
622 Main Street, Suite I 00
Buffalo, NY 14202
If you have any questions about the content of this letter, please contact Ms. Clark at 716-846-6236 or e-mail at email@example.com.
Ronald M. Pace
New York District