Food and Drug Administration staff from the Center for Biologics Evaluation and Research met with representatives from AABB to discuss topics of mutual concern regarding donor and patient safety and product manufacturing. Participants at the meeting expressed similar remarks on the value of ongoing discussions in these areas.
Age of blood at time of transfusion/storage of blood – In recent years the transfusion medicine community has revisited this topic and has had concerns due to results from observational studies correlating patient outcome to RBC storage. However, as preliminary results from randomized controlled clinical trials on the clinical impact of the age of transfused RBCs have been presented at professional meetings and demonstrated no significant differences in patient outcomes in fresher versus older stored RBCs, the concerns have been reduced. AABB plans a Research and Progress session at the 2015 Annual Meeting to further explore results of the ABLE (Age of Blood Evaluation Trial) and RECESS (Red Cell Storage Duration Study) studies. FDA participants acknowledged the decreased level of concern in several areas but noted other issues that could be worthy of a workshop, such as understanding what happens to red cells during storage, biomarkers that could predict oxygen delivery in vivo, and relevant issues related to donor characteristics.
Laboratory Developed Tests –Recognizing that the Center for Devices and Radiological Health is the lead Center at the FDA driving the regulatory framework described in the recently published draft guidance documents “Framework for Regulatory Oversight of Laboratory Developed Tests” and “Notification and Medical Device Reporting for Laboratory Developed Tests,” and that CDRH likely will not understand the impact of many of the proposals on transfusion medicine, AABB reiterated to the CBER representatives the concerns and recommendations that it recently submitted to the docket on behalf of its members. AABB noted that it did not make a distinction between serological or molecular methods used for compatibility testing for RBCs and platelets when responding to the open docket. Overall, it remains difficult to know the exact scope of the enforcement FDA is embarking upon, and how to identify which test, or alteration to a test, falls within the scope of the enforcement. This affects the notification requirements (eventually a registration requirement) and associated timelines. The proposed timelines associated with notification (registration) may be impossible to meet as it appears an LDT may be created during the search for compatible blood that needs to be transfused immediately.
Traditional LDTs are critical in the search for compatible blood and blood products for patients with complex antibody issues. The FDA has offered a narrow “definition” of the entities that may continue to enjoy enforcement discretion with respect to premarket review requirements for traditional LDTs. There are several elements to the definition. The second element, listed below would allow most transfusion services to continue using LDTs while blood center laboratories would have to stop such use. AABB participants at the meeting explained that this distinction should not be made since both entities are necessary to provide compatible blood to the patient and both are using the same tests, in some instances LDTs.
"Whether the LDT is both manufactured and used by a health care facility laboratory (such as one located in a hospital or clinic) for a patient that is being diagnosed and/or treated at that same health care facility or within the facility’s healthcare system”
According to the guidance document LDTs used in compatibility testing are categorized as High Risk; AABB recommended that the appropriate category is Low Risk due to the level of oversight and inspection already in place (e.g., CLIA, AABB, CAP, FDA). In addition, adverse event reporting via the device reporting process is duplicative with conflicting timelines for reporting that already occurs via the biological product deviation process. AABB noted that a new requirement is detrimental/error prone without added benefit to patients or any entity/system.
FDA representatives stressed that CBER is actively engaged in the discussions and review of comments submitted to the docket. In addition they reviewed venues for continued participation and provision of input by the public and encouraged AABB to watch for the classification panels that will be used to decide further action by the agency once the notification process closes. The panels will function in an open meeting process. If LDTs used for compatibility testing are thought to be Low Risk, rather than High Risk, then it is important for laboratories to fully explain the mitigating factors as well as factors that may “kick up” the level of risk. In addition a liaison (Cara.Tenebaum@fda.hhs.gov) is available in the Office of External Affairs at FDA who continues to assist stakeholders who want to provide additional input to the agency.
How to label RBCs with historical antigen test results – This remains an incompletely resolved issue but additional information was learned during the meeting. Originally the discussion started at the April 2012 AABB FDA Liaison Committee meeting due to variance requests that blood centers had submitted to the FDA. The blood centers were seeking an alternative to providing the historical antigen results on accompanying paperwork. The discussion revealed several areas that required further discussion and AABB established a work group that included FDA liaisons. The goal of labeling RBCs with historical results is to conserve expensive/rare anti-sera and discontinue performance of molecular assays at each donation. The opinion of the work group was presented to the FDA at the December 2012 BPAC; the BPAC consensus was in agreement with the expert opinion of the work group. AABB’s BBTS Standards Program Unit received the report of the work group and the 29th edition of Standards for Blood Banks and Transfusion Services was updated so that components could by labeled via label or tie tag:
5.8.4 Red Cell Antigens Other than ABO and RhD – Units may be labeled as antigen negative, without testing the current donation, if units from two previous separate donations were tested by the collection facility and found to be concordant.
However, as FDA had not responded in the affirmative to variance requests and had publicly stated that they intend to publicize their position via a guidance document, blood centers have not moved forward en masse to label, with the use of tie tags or labels, to take advantage of historical antigen results.
During this meeting AABB representatives learned that the FDA has approved standard operating procedures for use of tie tags for historical antigen results, without testing the current donation, if units from two previous donations were tested by the collection facility and found to be concordant. In addition, the establishments should have validated processes to confirm donor identification and accurate linkage of the current RBC donation to the historical result. The result should be identified as a historical result; the face label cannot be used, therefore the ISBT standards that were described at the BPAC meeting are not currently approved to be used. If reagents/assays other than FDA-approved/cleared are used this should be noted on the tie tag along with the results.
AABB actions early in the lifecycle of an event, prior to or in the absence of FDA recommendations – Participants reviewed several examples where AABB issued guidance or recommendations when it appeared that donor exposure to a particular infectious agent may affect the safety of the blood product. In some instances, AABB, which has the ability to quickly enact recommendations based on the available information and the flexibility to amend recommendations as needed based on changing information, acted prior to FDA, or in the absence of FDA guidance. Examples discussed included babesiosis, XMRV (xenotropic murine leukemia virus-related virus), CHIKV (chikungunya virus), and Ebola virus. Although AABB and the FDA may, at times, work on slightly different timelines their goals and objectives typically are in agreement and the outputs generally conform in the end. There was consensus that the process has worked well due to open communication supported by the presence of FDA liaisons on the Transfusion Transmitted Diseases Committee and the Donor History Task Force as well as direct communications between AABB and FDA.
The Emerging Infectious Diseases supplement to the August 2009 TRANSFUSION and the ongoing work of the DHTF to maintain and update the Donor History Questionnaire for blood donors were highlighted by FDA participants as highly cooperative and constructive projects. Also noted was the importance of Workshops, whether sponsored by AABB, FDA, or another organization, as a way to gather information and have a full conversation on a given subject. This is in contrast to a scheduled Advisory Committee meeting which has the purpose of “advising” the FDA on a particular issue, and does not provide the public with much advance notice of the discrete issue. FDA is not “advised” by Workshop information in order to take action on a matter in front of the agency, but can participate as an attendee or speaker, etc. and be informed.
Surveys were mentioned as a source of helpful information otherwise not available to the FDA. The agency appreciates blood establishment participation, whether it is through the RapidDoS programs, or surveys conducted by AABB and other organizations who then share results with the FDA.
Peter Marks, MD, PhD, Deputy Director, Office of the Center Director (OD), Center for Biologics Evaluation and Research (CBER)
Jay Epstein, MD, Director, Office of Blood Research and Review (OBRR), CBER
Ginette Y. Michaud, MD, Deputy Director, OBRR
Pauline Cottrell, CSO, Manufacturers Assistance and Technical Training Branch (MATTB), Office of Communications, Outreach and Development, CBER
Lynne Uhl, MD, President
Jean Otter, Vice President, Transfusion Medicine Standards & Accreditation, Regulatory
M. Allene Carr-Greer, Director, Regulatory Affairs
Theresa L. Wiegmann, Director, Public Policy, Special Counsel