January 31, 2006 CERTIFIED MAIL RETURN RECEIPT REQUESTED

Transcription

1 January 31, 2006 CERTIFIED MAIL RETURN RECEIPT REQUESTED Michael Mastromarino, D.D.S. CEO & Executive Director of Operations Biomedical Tissue Services, Ltd Center Avenue, Suite 300 Fort Lee, NJ Dear Dr. Mastromarino: The Food and Drug Administration (FDA or the agency) conducted an inspection of your establishment, Biomedical Tissue Services, Ltd. (BTS or Establishment), at 2125 Center Avenue, Suite 300, Fort Lee, New Jersey 07024, which manufactures human cells, tissues, and cellular and tissue-based products (HCT/Ps), between October 4 and 27, At the conclusion of the inspection, the FDA investigators issued you a Form FDA-483, Inspectional Observations. In addition to the inspection, the agency conducted a concurrent investigation of several funeral homes that provided you with potential donors of HCT/Ps for recovery. Our review of the information and records examined and collected during the inspection and investigation reveal that significant violations of Title 21, Code of Federal Regulations (21 CFR), Part 1271, issued under the authority of Section 361 of the Public Health Service Act (PHS Act) [42 U.S.C. 264], exist at BTS. The agency has determined that these deviations, because of their serious nature, constitute a danger to health. This Order to Cease Manufacturing and to Retain HCT/Ps relates exclusively to conduct occurring on or after May 25, 2005, the effective date of these regulations. We note that the FDA retains authority to pursue other actions and remedies. Therefore, pursuant to 21 CFR (a)(1) and (3), both you individually, and your Establishment, 1) must immediately cease all manufacturing until compliance with the regulations in 21 CFR Part 1271 has been achieved, and 2) must retain all HCT/Ps recovered on or after May 25, 2005 that are in your possession until they are disposed of as agreed by the agency or until the safety of the HCT/P is confirmed. Pursuant to 21 CFR (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. Deficiencies noted include, but are not limited to, the following: 1. You failed to implement the standard operating procedures (SOP or SOPs) that you have established for all steps that you perform in determining donor eligibility, as required by 21 CFR (a), and you failed to review the certificate of death for each donor, a relevant medical record, regarding risk factors for, or clinical evidence of, relevant communicable disease agents and diseases, as required by 21 CFR (a). More specifically, your standard operating procedure entitled "Donor Identification" requires that, when recovering HCT/Ps at a funeral home, you review the death certificate to confirm the eligibility of the donor. However, you recovered HCT/Ps from at least eight donors, obtained from --- different funeral homes, located in different states, in which you failed to review valid death certificates. The documents purporting to be the certificates of death for these donors were collected from BTS during our inspection, are not authentic death certificates issued by the state, and are inaccurate. For example:

2 A. You confirmed the eligibility of donor , who donated HCT/Ps at a funeral home in The donor is listed on the BTS version of the certificate of death as being 63 years of age, having died of acute myocardial infarction due to coronary artery disease, at ----pm on , whereas the State of issued certificate of death lists this donor as being 69 years of age, having died of multi-organ failure, due to liver dysfunction, which in turn was due to thrombosis, at ----pm on ; B. You confirmed the eligibility of donor , who donated HCT/Ps at a funeral home in The donor is listed on the BTS version of the certificate of death as being 44 years of age, having died of blunt trauma in a motor vehicle accident, at ----am on , whereas the State of issued certificate of death lists this donor as being 48 years of age, having died of congestive cardiac failure due to atherosclerotic cardiovascular disease, at ----am on ; C. You confirmed the eligibility of donor , who donated HCT/Ps at a funeral home in The donor is listed on the BTS version of the certificate of death as being 70 years of age, having died of cardio-pulmonary arrest due to acute myocardial infarction, at ---- pm on , whereas the State of issued certificate of death lists this donor as being 74 years of age, having died of complications from the intravenous administration of medication due to a radical resection of a , at ---- pm on ; D. You confirmed the eligibility of donor , who donated HCT/Ps at a funeral home in The donor is listed on the BTS version of the certificate of death as having died of cardiopulmonary arrest due to atherosclerotic heart disease, at ----pm on , whereas the State of issued certificate of death lists this donor as having died of cardio-pulmonary asystole due to sepsis and shock, at ----pm on ; E. You confirmed the eligibility of donor , who donated HCT/Ps at a funeral home in The donor is listed on the BTS version of the certificate of death as being 45 years of age, having died of blunt trauma due to a motor vehicle accident, at ----pm on , whereas the State of issued certificate of death lists this donor as being 41 years of age, with a cause of death which was undetermined pending additional studies, at ----pm on ; F. You confirmed the eligibility of donor , who donated HCT/Ps at a funeral home in The donor is listed on the BTS version of the certificate of death as having died of cardio-pulmonary arrest due to acute myocardial infarction, at ----pm on , whereas the State of issued certificate of death lists this donor as dying of probable ventricular fibrillation due to failure, as a consequence of disease, at ----am on ; G. You confirmed the eligibility of donor , who donated HCT/Ps at a funeral home in The donor is listed on the BTS version of the certificate of death as being 58 years of age, having died of acute myocardial infarction, at ----am on , whereas the State of issued certificate of death lists this donor as being 50 years of age, having died of diabetes mellitus and hypertension due to cardio-vascular disease, at ----pm on ; and H. You confirmed the eligibility of donor , who donated HCT/Ps at a funeral home in The donor is listed on the BTS version of the certificate of death as being 63 years of age, having died of acute myocardial infarction, at ----pm on , whereas the State of issued certificate of death lists this donor as being 79 years of age, having died of pneumonia due to a myocardial infarction, at ----pm on You failed to implement the SOPs that you have established for all steps that you perform in determining donor eligibility, regarding your assessment of risk factors for, or clinical evidence of, relevant communicable disease agents and diseases, as required by 21 CFR (a). Furthermore, you failed to create and maintain accurate records, as required by 21 CFR (d)(2) and 21 CFR (a). More specifically, your "Documenting the Recovery" SOP requires that, if the donor had been admitted to a health care facility immediately prior to death, you were to document the date and reason for admission; check the appropriate boxes regarding availability of donor history, physical, and discharge summary; check the appropriate box regarding surgeries; check the appropriate boxes regarding availability of lab results (including blood cultures, x-rays, and lung biopsies); and check the appropriate boxes regarding documentation of HIV, Hepatitis and Tuberculosis infection. However, your Medical Evaluation forms for donors , , , , , and (who donated HCT/Ps in different funeral homes located in different states), do not contain any of this information. Instead, you

3 incorrectly stated that these donors were not admitted to a health care facility immediately prior to death, which statements are contradicted by the state-issued certificates of death for each of these donors. 3. You failed to create and maintain accurate records, as required by 21 CFR (d)(2) and 21 CFR (a). More specifically: A. The Medical Evaluation forms created and maintained by you for the following six donors are inaccurate in that you state that the donors were not admitted to a health care facility immediately prior to death. In so doing, you also failed to adhere to the following SOPs: Documenting the Recovery SOP; Quality Assurance Audit of Donor Records SOP; Quality Assurance Check-Off Form; and Audit Check List. These six donors donated HCT/P at -----different funeral homes, located in different states. More specifically: i. the State of issued certificate of death for donor states that at the time of her death she was a patient at Hospital; ii. the State of issued certificate of death for donor states that at the time of his death he was a hospital inpatient at ; iii. the State of issued certificate of death for donor states that at the time of his death he was a patient at Hospital; iv. the State of issued certificate of death for donor states that at the time of her death she was a patient at Hospital; v. the State of issued certificate of death for donor states that at the time of his death he was a patient at Hospital; and vi. the State of issued certificate of death for donor states that at the time of her death she was a patient in the emergency room of Hospital. B. The records created and maintained by you for donor are inaccurate in that you state in your Certifying Physician Interview form that the donor was a 44 year old male who died as a result of a blunt trauma to the head region in a motor vehicle accident; your Circumstances of Death form states that the donor was a 44 year old male who was involved in a motor vehicle accident, sustained blunt trauma, and expired at the scene of the accident prior to medical intervention; and your Donor Physical Assessment form includes an incorrect schematic of the donor, showing fractures to the anterior and posterior portions of the skull, together with bruises or contusions to the anterior and posterior portions of the neck. These records are contradicted by the State of issued certificate of death, which states that the donor died of natural causes (congestive cardiac failure, resulting from atherosclerotic cardiovascular disease), at his home, at the age of 48. The only other significant condition which is listed as contributing to the death of the donor in the State of issued certificate of death is In creating and maintaining these inaccurate records, you have also failed to adhere to your "Documenting the Recovery" SOP, your "Quality Assurance Audit of Donor Records" SOP, your Audit Check List, and your Quality Assurance Check-Off form. C. The records created and maintained by you for donor are inaccurate in that you state in your Certifying Physician Interview form that the donor was a 45 year old female who suffered blunt trauma in a motor vehicle accident, and died at the scene of the accident prior to medical intervention; your Circumstances of Death form states that the donor was a 45 year old female who was involved in a motor vehicle accident, sustained blunt trauma to the head region, and expired prior to medical intervention; and your Donor Physical Assessment form includes an incorrect schematic of the donor, showing fractures to the anterior and posterior portions of the skull, together with bruises or contusions to the anterior and posterior portions of the neck. These records are contradicted by the State of issued certificate of death, which states that the donor died at her home, at the age of 41, was , and with an undetermined cause of death, pending additional studies. There were no other significant conditions listed as possibly contributing to the death of the donor in the state-issued certificate of death. In creating and maintaining these inaccurate records, you have also failed to adhere to your "Documenting the Recovery" SOP, your "Quality Assurance Audit of Donor Records" SOP, your Audit Check List, and your Quality Assurance Check-Off form. D. The records created and maintained by you for donor are inaccurate and incomplete in that your Certifying Physician Interview form for this donor fails to indicate the cause of death; your Circumstances of Death form for this donor incorrectly states that the donor was a 70 year old female, and fails to indicate the cause of death; your Medical/Social History Interview form incorrectly states that the donor never received an organ transplant; and your Donor Physical Assessment form for this

4 donor fails to show on the schematic that the donor had a surgical procedure to her immediately prior to her death, and also fails to show that the donor had undergone a transplant. These records are contradicted by the State of issued certificate of death, which states that the immediate cause of death of this donor was due to complications related to the intravenous administration of medication due to a The donor is also listed on the State of issued certificate of death as having undergone a status post-cadaver transplant for disease, and as having died at the age of 74. In creating and maintaining these inaccurate records, you have also failed to adhere to your "Quality Assurance Audit of Donor Records" SOP, your "Documenting the Recovery" SOP, your Audit Check List, and your Quality Assurance Check-Off form. E. The records created and maintained by you are inaccurate as concerns the identity of the funeral home from which donors , , and were obtained and at which HCT/P recovery procedures were performed for these donors. In your Donor Demographics forms for these donors you state that their recovery location was a funeral home in , , and you also state that the director of the funeral home provided you with a positive identification of these three donors. However, in an affidavit provided to the agency by the director of the funeral home, while he estimates that his funeral homes have provided between --- and ---- donors to BTS, they did not provide BTS with these three donors. In creating and maintaining these inaccurate records, you have also failed to adhere to your "Quality Assurance Audit of Donor Records" SOP, your "Documenting the Recovery" SOP, your Audit Check List, and your Quality Assurance Check-Off form. 4. You failed to implement the SOPs you established for donor eligibility determinations specifically for documenting and confirming the identity of the donors' next of kin, including your Donor Medical Social History Interview SOP, your Quality Control Review of Donor Records SOP, your Quality Assurance Audit of Donor Records SOP, your Audit Check List, and your Quality Assurance Check-Off form, all as required by 21 CFR (a), and you failed to create and maintain accurate records, as required by 21 CFR (d)(2) and 21 CFR (a), in that you have inaccurately and incompletely recorded the donors' next of kin information. More specifically: A. The records created and maintained by you for donor are inaccurate and incomplete in that your information on the donor's spouse differs from that found in the State of issued certificate of death. More specifically: i. while your Consent for Donation of Anatomical Gifts form for this donor lists the donor's spouse as the consenting next of kin, the donor's spouse is incorrectly listed as another individual, residing at an entirely different address than the donor; ii. while your Medical/Social History Interview form for this donor lists the interviewee as the donor's spouse, the interview form incorrectly identifies the donor's spouse and residential address; iii. iv. your Circumstances of Death form for this donor also incorrectly identifies the spouse; and the BTS version of the certificate of death for this donor is incomplete in that it does not list any surviving spouse, and does not indicate whether the donor was married. B. The records created and maintained by you for donor are inaccurate and incomplete in that your information on the donor's spouse differs from that found in the State of issued certificate of death. More specifically: i. while your Consent for Donation of Anatomical Gifts form for this donor lists the donor's spouse as the consenting next of kin, the donor's spouse is incorrectly listed as another individual, residing at an entirely different address than the donor; ii. iii. iv. while your Medical/Social History Interview form for this donor lists the interviewee as the donor's spouse, the interview form incorrectly identifies the donor's spouse and residential address; your Circumstances of Death form for this donor also incorrectly identifies the spouse; and the BTS version of the certificate of death for this donor is incomplete in that it does not list any surviving spouse, and does not indicate whether the donor was married. 5. You failed to implement the SOPs you established for donor eligibility determinations, as required by 21 CFR (a), and to assure the timely refrigeration of donors and recovery of HCT/P, as required by (a). You failed to recover HCT/P in a manner that does not cause contamination or crosscontamination during recovery, to adequately control environmental conditions, and to provide proper conditions for operations, all as required by 21 CFR , 21 CFR (a)(1), and 21 CFR

5 Furthermore, you failed to create and maintain accurate records, as required by 21 CFR (d)(2) and 21 CFR (a). Your SOPs require that donors be refrigerated within hours and that HCT/P excision begin within hours post cardiac asystole. However, you did not meet these standards for the following donors: A. your Donor Demographics form for donor states that the donor was " refrigerated within --- hours and tissue excision began within ---- hours post cardiac asystole" and that the donor s refrigeration time was at ----am on , which, according to the State of issued certificate of death's time of death (----pm on ), is more than 33 hours post-cardiac asystole. Also, according to your Tissue Recovery Log form for this donor, HCT/P excision of the donor began at ----pm on , almost 48 hours post-cardiac asystole. As a result, your Donor Demographics form is inaccurate; and B. your Donor Demographics form for donor states that the donor was " refrigerated within -- --hours and tissue excision began within ---- hours post cardiac asystole" and that the donor s refrigeration time was at , which, according to the State of issued certificate of death ( ), is almost 48 hours post-cardiac asystole. Also, according to your Tissue Recovery Log form for this donor, HCT/P excision of the donor began at ----pm on , more than 54 hours post-cardiac asystole. As a result, your Donor Demographics form is inaccurate. 6. You failed to implement SOPs you established to assure that HCT/P recovery takes place in a suitable environment, as required by 21 CFR (a). You failed to recover HCT/Ps in a manner that does not cause contamination or cross-contamination during recovery, and you failed to adequately control environmental conditions and to provide proper conditions for operations, all as required by 21 CFR , 21 CFR (a)(2), and 21 CFR Furthermore, you failed to create and maintain accurate records, as required by 21 CFR (d)(2) and 21 CFR (a). Your SOP requires that the HCT/P recovery site ensure a maintained and controlled, closed airflow system so that there is no direct access to the outside of the building. However, you recovered HCT/P from donors and at a funeral home in , that is not equipped with any refrigeration units in which to hold the deceased. The embalming room where HCT/P recovery took place was equipped with an exhaust fan that delivered air to the adjacent garage/outside. There was no air filtration system in the room. Moreover, you recorded in your Nonstandard Tissue Recovery Site Assessment form for these donors that the recovery site ensured a maintained and controlled, closed airflow system so that there was no direct access to the outside of the building. 7. You failed to implement SOPs you established for donor eligibility determinations, specifically to confirm whether an autopsy was performed, as required by 21 CFR (a). In particular, your Quality Control Review of Donor Records SOP requires that "[t]he team leader will assure a physical exam was performed and the information documented on the recovery paperwork is included in the donor chart " and your Physical Assessment of a Cadaveric Donor SOP requires that the team leader physically check the donor in their entirety. Furthermore, you failed to create and maintain accurate records, as required by 21 CFR (d)(2) and 21 CFR (a). Your Donor Demographics forms for donors and state that no autopsies had been performed on these donors, and the Donor Physical Assessment forms for these donors provide schematics of the donors which fail to show that autopsies had been performed. These documents are contradicted by the State of issued certificates of death for these donors, which confirm not only that autopsies were performed on these two donors, but also that the autopsy findings were available to complete the cause of death. The fact that an autopsy had been performed should have been obvious to you upon your physical assessment of the donors at the time of HCT/P recovery. The above-identified deficiencies are not intended to be an all-inclusive list of violations by you and your Establishment. Nevertheless, they indicate serious noncompliance with many of the regulations under 21 CFR Part 1271, which are designed to protect against the risks of communicable disease transmission. Of particular concern are the serious deficiencies involving: 1/ your failure to create and maintain accurate records; 2/ your failure to implement SOPs for all steps in determining donor eligibility;

6 3/ your failure to recover HCT/Ps in a manner that does not cause contamination or cross-contamination during recovery; and 4/ your failure to adequately control environmental conditions. These deficiencies involve donors from numerous funeral homes located in different states. Based on the foregoing, the agency finds that there are reasonable grounds to believe that HCT/Ps manufactured by you are violative because they were manufactured in contravention of the regulations under 21 CFR Part 1271 and, therefore, the conditions of manufacture of the HCT/Ps do not provide adequate protections against the risks of communicable disease transmission. Moreover, these deficiencies, including your failure to create and maintain accurate records, are so serious and widespread that FDA finds there are reasonable grounds to believe that they present a danger to public health. This letter confirms the telephone conversation on January 31, 2006, in which notice was given that, pursuant to 21 CFR (a)(3), you individually, and your Establishment, 1) must immediately cease all manufacturing, as defined in 21 CFR (e), until compliance with the regulations in 21 CFR Part 1271 has been achieved, and 2) must retain all HCT/Ps recovered on or after May 25, 2005 that are in your possession until they are disposed of as agreed by the agency or until the safety of the HCT/P is confirmed. Instructions were given at that time not to recover or ship HCT/Ps. Neither you, nor your Establishment, can resume operations without prior written authorization from FDA. Any shipment of HCT/Ps in violation of this order constitutes a violation of section 368 of the PHS Act [42 U.S.C. 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 (telephone: ). 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 Part 10, Subpart C. Sincerely, signature Jesse L. Goodman, M.D., M.P.H. Director Center for Biologics Evaluation and Research Effective Date: 31 January Time: 11:25 AM Eastern