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U.S. Department of Health and Human Services

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Enforcement Actions

Virginia Center for Reproductive Medicine 9/10/13

  

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 Baltimore District Office
Central Region
6000 Metro Drive
Baltimore, MD 21201-2199
Telephone: (410) 779-5455
FAX: (410) 779-5705 

WARNING LETTER
CMS#409387

 

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

September 10, 2013
 

Fady I. Sharara, MD, Medical Director
Virginia Center for Reproductive Medicine
11150 Sunset Hills Rd., Suite 100
Reston, VA 20190

 

Dear Dr. Sharara:

The Food and Drug Administration (FDA) conducted an inspection of your firm, Virginia Center for Reproductive Medicine located at 11150 Sunset Hills Rd., Suite 100, Reston, VA, on April 30, 2013; May 1-2, 2013; May 14-17, 2013; May 29, 2013; and June 12, 2013. During this inspection, FDA investigators 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 (42 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.    A specimen collected from directed semen donor (b)(4), (b)(6) March 1, 2012, tested reactive on a screening test for anti-HIV 1/2 + group O. A donor eligibility determination was not performed; however semen was recovered from donor (b)(4), (b)(6) on March 1, 2012.

b.    A specimen collected from directed semen donor (b)(4), (b)(6). on June 22, 2011, tested reactive on a screening test for anti-HBc. A donor eligibility determination was not performed; however semen was recovered from donor (b)(4), (b)(6) on June 22, 2011.

c.    A specimen collected from directed semen donor (b)(4), (b)(6) on March 2, 2012, tested reactive on a screening test for anti-HTL V -IIII. A donor eligibility determination was not performed; however semen was recovered from donor (b)(4), (b)(6) on April 6, 2012 and July 27, 2012.
 

2.    Failure to determine as ineligible a donor who is identified as having a risk factor for, or clinical evidence of, any of the 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)]. For example:
 

a.    Directed semen donors (b)(4), (b)(6). answered "yes" to the question on the Donor Medical History form, "Have you had sex with another man in the preceding five years?" These donors were not determined to be ineligible.

b.    Directed semen donor (b)(4), (b)(6), answered "no" to the question on the Donor Medical History form regarding having lived cumulatively for five years or more in Europe from 1980 until the present. On the donor's New Client Questionnaire Application for a gestational carrier he listed Germany as his birthplace, indicated that he had been a permanent resident of Germany and provided a German address as his current residence. Donor (b)(4), (b)(6) was not determined to be ineligible.
 

3.    Failure to prominently label an HCT/P, made available for limited use from an ineligible donor, with the Biohazard legend and the statement "WARNING: Advise patient of communicable disease risks," and in the case of reactive test results, "WARNING: Reactive test results for (name of disease or disease agent)." [21 CFR 1271.65(b)(2)]. For example:
 

a.    The following donors tested reactive on a screening test for a relevant communicable disease agent or disease, however their semen was not labeled with a Biohazard legend or the appropriate warning statements:

i. Directed donor (b)(4), (b)(6) tested reactive for anti-HIV-I/2+O on May 5, 2009. Semen was recovered from donor (b)(4), (b)(6) the same day and on March 1, 2012. 

ii. Directed donor (b)(4), (b)(6) tested reactive for anti-HBc (IgG+IgM) on January 14, 2009. Semen was recovered from donor (b)(4), (b)(6) the same day. 

iii. Directed donor (b)(4), (b)(6) tested reactive for anti-HTLV-112 on March 2, 2012. Semen was recovered from donor (b)(4), (b)(6) on April 6, 2012 and July 27, 2012. 

iv. Directed donor (b)(4), (b)(6) tested reactive for anti-HBc (IgG+IgM) on June 22, 2011. Semen was recovered from donor (b)(4), (b)(6) the same day.
 

b.    During donor screening, the following donors were identified as having a risk factor for relevant communicable disease agents or diseases. Their semen was not labeled with a Biohazard legend or the appropriate warning statements:

i. Directed semen donors (b)(4), (b)(6) answered "yes" to the question "Have you had sex with another man in the preceding five years?" on the Donor Medical History form.
 

ii. Directed semen donor (b)(4), (b)(6) reported having been born in Germany and residing in that country for most of his life. 

4.    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:
 

a.    Eligibility determinations were not performed for three directed oocyte donors.
 

i. Oocytes were recovered from directed donor (b)(4), (b)(6) on April 6, 2012 and July 27, 2012.
 

ii. Oocytes were recovered from directed donor (b)(4), (b)(6) on May 4, 2012. 

iii. Semen was recovered from directed donor (b)(4), (b)(6) on November 9, 2012.
 

b.    An eligibility determination was made for anonymous oocyte donor (b)(4), (b)(6) without a review of the results of donor testing. The sample for testing was collected on November 2, 2012; the same day the donor eligibility determination was made. Oocytes were recovered from donor (b)(4), (b)(6) on November 6, 2012.
 

c.    The section of the Donor Eligibility form where the Responsible Person makes the eligibility determination and signs the form was not completed for anonymous oocyte donor (b)(4), (b)(6) The Medical Director had signed the form at the bottom indicating he had made the eligibility determination, although it had not been completed. Oocytes were recovered from donor (b)(4), (b)(6) on June 22, 2012.
 

d.    An eligibility determination was made for anonymous oocyte donor (b)(4), (b)(6) without a review of the results of donor screening. Donor (b)(4), (b)(6) was determined eligible on December 7, 2011; however the Donor Medical History Interview form was completed on December 8, 2011.
 

5.    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)]. Specifically, testing for relevant communicable diseases including HIV -112, hepatitis B, hepatitis C, syphilis, gonorrhea, and chlamydia was not performed for anonymous oocyte donor (b)(4), (b)(6). The donor was determined to be eligible on November 23, 2012 and oocytes were recovered the same day. Records of communicable disease testing for this donor could not be located in the donor files or at the reference laboratory which was contracted to perform the donor testing.
 

6.    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)]. 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 donor medical history interview and a current report of the physical examination of a living donor. For example:
 

a.    There was no documentation of either a donor medical history interview or a physical examination for seven directed semen donors. The donors were allowed to donate without eligibility being determined. 

b.    There was no documentation of either a donor medical history interview or a physical examination for a directed semen donor and an anonymous oocyte donor. The donors were determined to be eligible and were allowed to donate.
 

c.    There was no documentation of a donor medical history interview for five anonymous oocyte donors. The donors were determined to be eligible and were allowed to donate. 

d.    There was no documentation of a physical examination for directed semen donor (b)(4), (b)(6) The donor was determined to be eligible on January 24, 2011.
 

7.    Failure to provide a summary of records to accompany an HCT/P, that contains a listing and interpretation of the results of all communicable disease tests performed [21 CFR 1271.55(b)(2)]. For example:

a.    The summary of records currently in use does not list the HBV PCR test performed as part of the MPX PCR Series which includes testing for HIV, HCV, and HBV.

b.    The summary of records currently in use does not always contain an interpretation of results of communicable diseases performed. For example: Oocytes were recovered from donor (b)(4), (b)(6) on January 26, 2011 and from donor (b)(4), (b)(6) on June 22, 2011. There was no interpretation of the results of communicable disease testing in the summary of records accompanying the donated HCT/Ps.
 

8.    Failure to have the summary of records that was used to make the donor eligibility determination accompany an HCT/P at all times [21 CFR 1271.55(a)(3)]. For example, HCT/Ps recovered from one anonymous oocyte donor, three directed oocyte donors, and thirteen directed semen donors were not accompanied by a summary of records. 

9.    Failure to keep HCT/Ps in quarantine, as defined by 21 CFR 1271.3(q), until completion of the donor eligibility determination [21 CFR 1271.60(a)]. Specifically, according to your Laboratory Director, storage tank 5 is designated as the storage tank for quarantined tissue. An eligibility determination was not performed for directed semen donors (b)(4), (b)(6) whose semen was documented as being stored in storage tank 3; or for donor (b)(4), (b)(6) whose semen was documented as being stored in storage tank 4.
 

10.    Failure to prominently label an HCT IP, for which a donor eligibility determination was not performed, with the appropriate warning statements [21 CFR 1271.90(b)]. Specifically, semen recovered from five donors for use with a sexually intimate partner, and for which a donor eligibility determination was not performed, were not prominently labeled with the statements ''NOT EVALUATED FOR INFECTIOUS SUBSTANCES" and "WARNING: Advise recipient of communicable disease risks."

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 response dated July 17, 2013, which provides a response to FDA's inspectional observations. We have reviewed the corrective actions outlined in the response and we have determined that they are inadequate to address our concerns.

We have specific comments regarding your response, as follows:

Your response to several of the inspectional observations cited in the FDA-483 demonstrates a lack of understanding of the applicable regulatory requirements. For example, in your response to FDA-483 Observation 1, you stated that directed semen donor (b)(4), (b)(6) who tested reactive on a screening test for anti-HIV-1/2, had a negative confirmatory test for HIV. As required under 21 CFR 1271.80(d)(1), you must determine to be ineligible, a donor whose specimen tests reactive on a screening test for a communicable disease agent, in accordance with 1271.85. Use of HCT/Ps from an ineligible donor is not prohibited in the case of a directed reproductive donor, provided the HCT/P from the donor is properly labeled with the appropriate warning labels.

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/GuidanceComplianceRegulatorylnformation/Guidances/CellularandGeneTherapy/ucm072929.htm) discusses the use of confirmatory tests and states, "You should consider performing confirmatory tests when a positive or reactive screening test result is received for such purposes as donor counseling or investigating discordant test results. However, if you perform a confirmatory test, negative or nonreactive results on a confirmatory test would not override a positive or reactive screening test."

Additionally, in regard to FDA-483 Observation 1, we are concerned about your use of the "Departure from Procedure Documentation Form." We would like to clarify that under 21 CPR 1271.47(d), "You must record and justify any departure from a procedure relevant to preventing risks of communicable disease transmission at the time of its occurrence. You must not make available for distribution any HCT/P from a donor whose eligibility is determined under such a departure unless a responsible person has determined that the departure does not increase the risks of communicable disease transmission through the use of the HCT/P." In the Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) (August 27, 2007), FDA clarifies that a departure from procedures is an "intended change from an established procedure, including a standard operating procedure (SOP), which occurs before the HCT/P is distributed, and is consistent with applicable regulations and standards."

A donor eligibility determination, which includes testing in accordance with 21 CPR 1271.80 and 1271.85, and donor screening in accordance with 21 CPR 1271.75, is required for all anonymous and directed reproductive donors of cells or tissue. As stated above, use of HCT/Ps from an ineligible donor is not prohibited in the case of a directed reproductive donor, provided the HCT/P from the donor is properly labeled, and you document that you notified the physician using the HCT/P of the results of testing and screening (1271.65(b)).

Please note, a departure from procedures should not be used to justify violations of the regulations in 21 CPR 1271 prior to or after an HCT/P has been transferred. The regulations under 21 CPR 1271 do not allow for recipients to consent to the receipt of HCT/Ps from an ineligible anonymous reproductive donor.

Your responses to the deficiencies cited in Observations 5, 6, 8, and 9 do not address the inadequacies found in the donor screening and relevant communicable disease testing performed in your facility. You did not discuss plans to review donor records for previous HCT/P donors to determine whether additional violations exist. You also did not address the increased risk of communicable disease transmission for HCT/Ps remaining in storage at your firm.

You should take prompt action to correct the violations addressed in this letter and prevent their recurrence. Failure to promptly correct these violations may result in regulatory action being initiated by the FDA without further notice. 

We request that you notify this office in writing, within fifteen (15) working days of receipt of this letter, of specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again. If corrective action cannot be completed within fifteen (15) working days, state the reason for the delay and the timeframe within which the corrections will be completed.
 

Please send your reply to the Food and Drug Administration, Attention: Ms. Evelyn Bonnin, District Director. If you have questions regarding any issues in this letter, please contact Compliance Officer, CDR Rochelle B. Young, RPh, MSA at 410-779-5437.
 

Sincerely,
/S/

Evelyn Bonnin
Baltimore District Director