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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Reproductive Medicine & Fertility Center of Southern Colorado LLC 10-Jun-08

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

Public Health Service
Food and Drug Administration

 

Denver District Office
Bldg. 20-Denver Federal Center
P.O. Box 25087
6th Avenue & Kipling Street
Denver, Colorado 80225-0087
Telephone: 303-236-3000
FAX: 303-236-3100


June 10, 2008

WARNING LETTER

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Paul C. Magarelli, M.D., Ph.D.
Medical Director
Reproductive Medicine & Fertility Center of Southern Colorado, LLC
265 Parkside Drive, Suite 200
Colorado Springs, CO 80910

Ref.# - DEN-08-15

Dear Dr. Magarelli:

The Food and Drug Administration (FDA) conducted an inspection of your firm, located at 265 Parkside Drive, Suite 200, Colorado Springs, Colorado, between March 6 and March 14, 2008. During this inspection, the FDA investigator found 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 (CFR), 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 a Form FDA-483 were presented 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 test specimens from anonymous or directed reproductive donors 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)]. Specifically, three anonymous oocyte donors (donors #[redacted], #[redacted] and #[redacted] were tested for relevant communicable disease agents (listed in 21 CFR 1271.85(a) and (c)) by a laboratory that did not use FDA-licensed, approved, or cleared donor screening tests:

a. Oocytes were recovered from anonymous donor #[redacted] on January 18, 2008 and were fertilized with semen from the recipient's [redacted] partner. Two resulting embryos were transferred to the recipient on January 21, 2008.

b. Oocytes were recovered from anonymous donor #[redacted] on February 24, 2008 and were fertilized with the semen from the recipient's [redacted] partner. Eleven resulting embryos were cryopreserved for future use.

c. Oocytes were recovered from anonymous donor #[redacted] on December 7, 2007 and were fertilized with semen from an anonymous donor. Four resulting embryos were transferred to recipient [redacted] on December 10, 2007.

2. Failure to screen an anonymous or directed reproductive 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 1271.75(a)]. Specifically:

a. Records for nine anonymous oocyte donors (#[redacted] and #[redacted], did not include adequate documentation of a donor medical history interview, as defined in 21 CFR 1271.3(n) (required as relevant medical records under 21 CFR 1271.3(s)). The "Donor Oocyte Questionnaire" used was an outdated version of the form instead of the updated version created by your firm in May 2005. As a result, there was no documentation related to risk factors for the relevant communicable disease agents listed in 21 CFR 1271.3(r). Oocytes were recovered from all nine donors and were fertilized and transferred to recipients as embryos or were cryopreserved for future use.

b. Records for four anonymous oocyte donors #[redacted] and #[redacted], who were repeat donors, did not include documentation of a complete donor screening or abbreviated donor screening (if within six months of a complete screening) prior to each oocyte recovery procedure. Specifically:

i. A "Donor Oocyte Questionnaire" was administered to anonymous donor #[redacted] on February 7 2007. On August 24, 2007, oocytes were recovered from donor #[redacted] and were fertilized and transferred as embryos to a recipient. On January 18, 2008, oocytes were recovered from donor #[redacted] and were fertilized and transferred as embryos to a recipient. Donor screening was not performed prior to these two oocyte recovery procedures to determine if there were changes in the repeat donor's medical/social history since the previous screening.

ii. A "Donor Oocyte Questionnaire" was administered to anonymous donor #[redacted] on July 15, 2006 prior to oocyte recovery on November 5, 2006. Oocytes were recovered from donor #[redacted] on four subsequent occasions (January 24, 2007, May 12, 2007, August 30, 2007, and February 20, 2008) and were fertilized and transferred as embryos to four recipients. Donor screening was not performed prior to the four subsequent oocyte recovery procedures to determine if there were changes in the repeat donor's medical/social history since the previous screening.

iii. A "Donor Oocyte Questionnaire" was administered to anonymous donor #[redacted] on August 4, 2006. On July 19, 2007, oocytes were recovered from donor #[redacted] and were fertilized and transferred as embryos into a recipient. On January 19, 2008, oocytes were recovered from donor #[redacted], and were fertilized and transferred as embryos into a recipient. Donor screening was not performed prior to the two oocyte recovery procedures to determine if there were changes in the repeat donor's medical/social history since the previous screening.

iv. A "Donor Oocyte Questionnaire" was administered to anonymous donor #[redacted] on June 10, 2006. Oocytes were recovered from donor #[redacted] on three occasions (March 28, 2007, June 17, 2007, and October 2, 2007) and were fertilized and transferred as embryos to two recipients. Donor screening was not performed prior to the three oocyte recovery procedures to determine if there were changes in the repeat donor's medical/social history since the previous screening.

3. Failure of a responsible person to determine and document the eligibility of an anonymous or directed donor of reproductive cells or tissue [21 CFR 1271.50(a)]. Specifically, no documentation was found during the review of three anonymous oocyte donor records to substantiate that a responsible person from your firm had determined the donors to be eligible prior to donation.

a. Oocytes were recovered from donor #[redacted] on five occasions; however there was no documentation that the donor was determined to be eligible prior to four oocyte recovery procedures (November 5, 2006, May 12, 2007, August 30, 2007, and February 20, 2008). Oocytes collected during all four procedures were fertilized and transferred to four recipients.

b . Oocytes were recovered from donor #[redacted] on November 3, 2006, however there was no documentation that the donor was determined to be eligible. Three oocytes were fertilized with semen from the recipient's partner and were transferred to the recipient on February 23, 2007.

c. Oocytes were recovered from donor #[redacted] on July 19, 2007, however there was no documentation that the donor was determined to be eligible. Thirty-four oocytes were fertilized with semen from both the recipient's partner and an anonymous semen donor and three embryos were transferred to the recipient on July 22, 2007.

4. Failure to establish and maintain procedures for all steps that you perform in testing, screening, determining donor eligibility, and complying with all other requirements of Subpart C "Donor Eligibility" in 21 CFR Part 1271. "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's standard operating procedures do not address all steps required for donor screening and determining donor eligibility, including, but not limited to: (1) donor screening for risk factors for, or clinical evidence of relevant communicable disease agents and diseases; and (2) the criteria used to determine donor eligibility and ineligibility.

The deviations identified above are not intended to provide an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure that your establishment complies with all applicable requirements of FDA regulations. You are responsible for reviewing all your firm's operations to assure you are in compliance with all applicable FDA regulatory requirements. You should take prompt action to correct these deviations and to prevent their recurrence. Failure to do so may result in further regulatory action.

We acknowledge receipt of your letter dated March 31, 2008, and your updated response letter dated May 12, 2008, describing corrective actions you have taken in response to FDA's inspectional observations. Our review of your May 12, 2008 response found it provided more complete documentation of corrective actions you have taken in response to our inspectional observations, but it still fails to adequately address all of our concerns. Some of the documentation provided in the May 12, 2008 response fails to adequately address eligibility of the donors, as described below.

In your May 12, 2008 response to Observation 2 on the FDA-483, you indicate you received completed screening questionnaires for high risk behavior from all of the nine donors who were not properly screened prior to donation. The screening questionnaire attached under attachment 3 for donor #[redacted] shows the donor answered "Yes" to the question, "In the past 3 years have you had [sic] contact with someone else's blood?" However, there was no documentation of follow-up questions to clarify the conditions under which the individual had this contact and whether or not this made the donor eligible or ineligible. Additionally, the screening questionnaire for donor #[redacted] shows the donor answered "Yes" to the question, "In the past 3 years have you lived with or had sexual contact with a person who has hepatitis?" Comments were made on the document to address receipt of a tattoo in the past 3 years and to the donors travel outside of the United States since 1980; however, there are no comments on the screening document to clarify whether the positive, response to living with or having sexual contact with a person with hepatitis made the donor eligible or ineligible to donate. These donors appear to have been determined to be eligible based on the responses provided in the questionnaires.

Under 21 CFR 1271.75(a), you must screen a donor of cells or tissue by reviewing the donor's relevant medical records and asking questions about the donor's medical history and relevant social behavior, including risk factors for relevant communicable disease agents and diseases. FDA's "Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) (August 2007) [http://www.fda.gov/cber/gdlns/tissdonor.htm] describes conditions and behaviors that increase a donor's relevant communicable disease risk and states that donors who exhibit one or more conditions or behaviors listed in the guidance should be determined ineligible. Included within this list (items IV.E. 6 and 9) are "Persons who have been exposed in the preceding 12 months to known or suspected HIV, HBV, and/or HCV-infected blood through percutaneous inoculation (e.g., needle stick) or through contact with an open wound, non-intact skin, or mucous membrane ...", and, "Persons who have lived with (resided in the same dwelling) another person who has hepatitis B or clinically active (symptomatic) hepatitis C infection in the preceding 12 months ....". Since it appears donor #[redacted] and [redacted] were not questioned further regarding the date of, and the situation surrounding, their contact with another person's blood or their contact with someone positive for hepatitis, respectively, your firm may not be able to confirm the donors' eligibility.

In addition, documentation of the third party review audit of donor charts, included as attachment 8 of the May 12, 2008 response, was missing information in regard to donors #[redacted] and [redacted]. In your response to this letter, please describe any additional corrective actions you have taken and provide complete documentation to demonstrate that the corrective actions are being appropriately implemented.

We request that you notify this office in writing, within fifteen (15) working days of receipt of this letter, with further details of the specific steps you have taken to correct the noted violations and to prevent their recurrence. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time frame within which the corrections will be completed.

Your reply should be sent to Nancy G. Schmidt, Compliance Officer, Food and Drug Administration, Denver District, P.O. Box 25087, Denver, Colorado 80225-0087. If you have any further questions, please feel free to contact Ms. Schmidt at (303) 236-3046.

Sincerely,

/S/

H. Thomas Warwick
Denver District Director