Minutes
Meeting between FDA and ASRM
Regarding Current Good Tissue Practice Issues
April 16, 2001
WOC-1, Conference Room 2
Present:
FDA: CBER; Antonio Pereira, Jay Epstein, Astrid Szeto, Kay Lewis, Jill Warner, Phil Noguchi, Deb Hursh, Joyce Frey, Jerome Davis, Martha Wells, OCC; Areta Kupchyk
External: Jacob Mayer, ASRM Public Affairs Committee; Sean Tipton, ASRM Public Affairs Director; Ben Younger, ASRM Executive Director; David Hoffman, SART President; Vicki Girard, Hogan and Hartson
The American Society for Reproductive Medicine (ASRM) requested this meeting with FDA to discuss the proposed regulation on "Current Good Tissue Practice for Manufacturers of Human Cellular and Tissue-Based Products; Inspection and Enforcement", published for public comment on January 8, 2001 as it applies to the practice of reproductive medicine. The purpose of the meeting was to understand FDA's intent on specific sections of the proposed regulation to be able to respond effectively to the public docket.
ASRM started the meeting with a discussion of general concerns that reproductive medicine is unique and the provisions of the regulation do not appear to apply because it is designed to apply to all tissues and cells. Reproductive medicine is focused on infertility treatment of couples where the concepts of product and manufacturing are not relevant. ASRM requested that flexibility be addressed as related to reproductive practices to assure that access is not impaired. FDA explained that it has responded to the use of the word product in the preamble and the revised title for the final rule on "Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment Registration and Listing", published on January 19, 2001. The term manufacture is considered a term of art and is also discussed in the final rule as pertaining to the activities or steps involved in preparing a cell or tissue for transplantation. Though many comments to the docket were received concerning this definition, no alternative was suggested and FDA was unable to come up with a better term.
ASRM requested clarification on how the prohibition on pooling (1271.220c) would apply to the practice of reproductive medicine such as the combination of egg and sperm from separate donors, and how does pooling apply to embryos stored in liquid nitrogen. FDA responded that under the proposed rule, combining a sperm and an egg would not be considered pooling, however pooling of sperm from different donors for an insemination would. ASRM indicated that this is not current practice though there is no industry standard prohibiting this practice. They requested that flexibility be considered for allowing pooling of embryos from different donor oocytes for an implantation when the situation is warranted. FDA discussed that liquid nitrogen storage of embryos in separate vials in the same liquid nitrogen tank would not be considered pooling under the proposed rule.
ASRM expressed concern with application of retention, recall and destruction pertaining to embryos. They explained that the couple and not the clinic owns the embryo. Even when known problems are identified such as possible CJD contamination of culture media, the clinic can only recommend disposition. Oocytes present similar issues as ownership is transferred immediately from the donor to the recipient. Once oocytes can be reliably frozen like sperm the issues of ownership will become easier. FDA explained that an Order for Retention, Recall, and Destruction is one of a number of different enforcement actions the agency could pursue depending on the facts and circumstances surrounding a case. FDA stated that it's possible that the agency could order a firm to retain and/or recall tissue, without ordering destruction of the tissue. FDA also clarified that the mere notification of a consignee could be construed as a recall.
ASRM identified process validation as a term that is incompatible with reproductive practices. Use of embryos to validate a process is generally unacceptable and banned if using public funding and animal studies are rare since there is no support for such research. FDA indicated that validation should apply to the steps and procedures used in preparing tissue for use such as cryopreservation, and cleaning.
ASRM expressed concern on the issue that the GTP's appear to go beyond communicable disease issues and focuses on outcome issues such as success rates. ASRM believes that there is a lack of known disease transmission from oocytes and embryos and that the GTPs go beyond the risk/benefit approach initially proposed by FDA. Their concern is that FDA will use success rates in assessing GTP's for a specific clinic. FDA explained that the economic assessment section in the proposed rule is required to address the effects of the rule regardless of whether their intended purpose. FDA stated that it would not be assessing success rates on inspection.
ASRM requested clarification on how FDA will apply "adverse reactions" to reproductive tissue. This could be problematic as it could encompass spontaneous miscarriages, ectopic pregnancies and non-pregnancy. Similarly "product deviation" could be problematic as it could encompass eggs that may not fertilize. FDA explained that the proposed rule limits adverse reactions to those that result in permanent impairment or damage or necessitates medical or surgical intervention. FDA agreed that further examination of how these concepts should apply to reproductive tissue was warranted.
ASRM stated that the proposed requirements for labeling can not be applied to some reproductive tissues because for many donated embryos the donors name is on the frozen straw and can't be taken off. Also the information required would not fit on these straws. FDA explained that labeling included accompanying materials so that not all information would have to be on the vial or straw containing the tissue.
Concern was also expressed by ASRM with overlapping regulations and the need for multiple inspections. SART currently lists 367 fertility centers as members (15 other non-member establishments are known) and requires certification through CAP (every 2 years), JCAHO (every 3 years) or New York State. Membership also requires that success rate data be submitted to CDC every year. CDC and SART audit the success rate information from 10% of these establishments yearly. FDA discussed current inspectional policies that take into consideration the certification status of an establishment if known
ASRM requested clarification on what facilities are expected to register in 2003 and be subject to the regulations. Would all ob-gyn practices that perform inseminations be regulated or just the ART facilities? If a facility utilizes purchased sperm that is shipped to them, would they be regulated. FDA explained that several exceptions to the regulation that pertain to reproductive practices are found in the final rule in 1271.15. These include if the establishment only recovers reproductive cells or tissue and immediately transfers them into a sexually intimate partner of the cell or tissue donor. The 1271.15d exemption for establishments if they only receive or store purchased sperm would also apply. Concern was also raised by ASRM on potential liability on already collected tissue. FDA explained that the regulations would not apply to tissue procured before the effective date. FDA explained that there is a Q and A on the CBER web site concerning registration and an email address is given to request information.
ASRM suggested that industry drafted standards be utilized as a way of leveraging resources. They proposed that ASRM explore drafting such guidance based on industry standards and certification requirements for the elements in the GTPs. FDA expressed enthusiasm for the idea of ASRM developing reproductive tissue specific guidance for GTP's requirements indicating that there are precedents for FDA reviewing and then issuing such guidances under appropriate administrative procedures as FDA guidance. ASRM indicated that they would review this concept and discuss it further with FDA.