Food and Drug Administration staff from the Center for Biologics Evaluation and Research (CBER) met with AABB's FDA Liaison committee to discuss topics of mutual concern regarding donor and patient safety and product manufacturing. The committee includes liaisons from AABB, the Advanced Medical Technology Association, America's Blood Centers, the American Red Cross, the American Society for Apheresis, the Armed Services Blood Program and the College of American Pathologists.
Peter Marks, MD, PhD, noted the value of dialogue between the FDA and members of the transfusion medicine community and expressed appreciation on behalf of the FDA for the opportunity provided by AABB. Ginette Michaud, MD, introduced several new employees of the Office of Blood Research and Review (OBRR) in attendance at the meeting: Peyton Hobson, PhD, Deputy Director, Division of Emerging and Transfusion Transmitted Diseases (DETTD); David Leiby, PhD, Chief, Product Review Branch, DETTD; Richard McBride, Chief, Blood and Plasma Branch, Division of Blood Components and Devices. Dr. Michaud also provided updates on several topics of interest.
Gilliam Conley provided a brief update on Program Alignment Efforts of the Office of Compliance and Biologics Quality, especially noting the Biologics Action Plan and the BioResearch Monitoring Plan. He also noted the following:
AABB President, Lynne Uhl, MD, provided an overview of several AABB initiatives and priorities.
Dr. Uhl reminded participants that the use of red blood cell (RBC) units labeled with historical antigen test results permits rapid selection of RBC units from inventory. However, unit labeling restricted to a tie-tag affixed externally to the unit, rather than use of ISBT 128 labeling, is a lost opportunity to promote improved safety of transfusion practice. AABB continues to encourage the FDA to move forward expeditiously with guidance 1) that includes the use of ISBT 128 (face labels) to provide historical results of red cell antigen typing, and 2) does not require repeat testing for the labeled antigen. The December 2012 Blood Products Advisory Committee and the 29th edition of AABB Standards for Blood Banks and Transfusion Services support such a move.
Requirements for Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use, Final Rule, published May 22, 2015
Hemoglobin levels – New requirements [21 CFR 630.10(f)(3)] in the rule will increase the minimum hemoglobin standard for male donors to 13.0 g/dL, effective May 23, 2016, and retain 12.5 g/dL for female donors. Establishments may elect to collect female donors with hemoglobin levels as low as 12.0 g/dL provided the establishment takes "additional steps to assure that this alternative standard is adequate to ensure that the health of the donor will not be adversely affected due to the donation, in accordance with a procedure that has been found acceptable for this purpose by FDA."
The Committee discussed the optional hemoglobin standard for female donors with FDA participants with the goal of reaching an understanding regarding the minimum elements that could be defined in establishment standard operating procedures (SOPS) and would be acceptable to the FDA. The FDA did not establish minimum standards in the Final Rule, as several related studies concerning ferritin testing and iron supplementation were still ongoing at the time. AABB suggested the formation of a work group, with FDA liaisons, charged with exploring acceptable elements aimed at ensuring the health of female donors who could be collected with hemoglobin levels as low as 12.0 g/dL. A determination of such minimal elements would have to take into account that blood establishments will require flexibility to implement programs that work best in their own environment. FDA representatives agreed that the output of a work group could help the process for blood establishments that want to prepare a submission for the FDA.
Pulse – New language [§630.10(f)(4)] in the rule is of concern to blood establishments due to the impact it will have on management of healthy blood donors who are currently accepted for blood donation through use of SOPs that have been reviewed/approved by the FDA. "The donor's pulse must be regular and between 50 and 100 beats per minute. A donor with an irregular pulse or measurements outside these limits may be permitted to donate only when the responsible physician determines and documents that the health of the donor would not be adversely affected by donating." Discussion of this new requirement for donor evaluation on page 29866 of the published rule (Federal Register Notice) uses one example, several times, of a well-recognized healthy donor who falls outside the range of bpm established in the rule/Code of Federal Regulations. The example used is that of a trained athlete.
The Committee reviewed SOPs currently used by blood establishments to accept these healthy athletic donors for blood donation even though their measured pulse may fall outside the bpm range the blood centers have in their SOPs for allogeneic donors. The new CFR language will likely require these valuable, healthy blood donors to stand to one side until a determination and documentation can be obtained by contacting the responsible physician. In many instances, perhaps the majority of times, the donors will be turned away and asked to come back another day. Additionally, the current language does not specify that the determination and documentation can apply to future donations. FDA participants asked questions to more fully understand the SOPs that are used and responded that the FDA still had the issue under consideration.
Autologous donors – §630.20 Exceptions for certain ineligible donors includes (a) "The donation is for autologous use only as prescribed by the donor's physician…and the responsible physician determines and documents that the donor's health permits the collection procedure." As was similarly stated in the discussion of pulse above, blood establishments are very familiar with managing donors who have been prescribed autologous donation by their physicians. Blood establishment SOPs ensure that the health of the donor permits collection of blood even when he or she does not meet the criteria of an allogeneic donor.
The Committee discussed with the FDA the potential for continued use of SOPs for management of autologous donors rather than a telephonic or off-site consultation for each autologous donor that does not meet allogeneic requirements. FDA participants asked questions to more fully understand the SOPs that are used and afterward noted that they will give the issue additional consideration.
Directed donations – Other language in §630.20 Exceptions for certain ineligible donors includes (c) "The donation is restricted for use solely by a specific transfusion recipient based on documented exceptional medical need, and the responsible physician determines and documents that the donor's health permits the collection procedure, and that the donation presents no undue medical risk to the transfusion recipient." The discussion relevant to this section is found on page 29876 of the published rule (Federal Register Notice). "We have not included the reference to donors deferred under § 610.41 because of a reactive screening test for a relevant transfusion-transmitted infection in final § 630.20. We determined that the provision was unnecessary to include here because §§ 610.40(h)(2)(i) and 610.41(a)(5) already authorize autologous collections from reactive donors, and §§ 610.40(h)(2)(ii) and 610.41(a)(2) and (3) authorize plasmapheresis collections under a special collection program. For a collection from a reactive donor outside these provisions, a blood establishment would first file a request under § 640.120."
The Committee and FDA discussed issues surrounding the need blood establishments have to release units with reactive screening tests (e.g., anti-HTLVI/II, anti-HBc, syphilis, or Trypanosoma cruzi antibodies) in a directed donor situation. Committee participants did not have numerical data on frequency of these releases, but establishment medical directors, when asked, could recount the occasion(s) when the units in question were released to meet the needs of a specific transfusion recipient, usually newborns with thrombocytopenia. The Committee asked the FDA to consider how the agency will manage review of the requests under § 640.120 prior to the collection of the donor and also noted that guidance is needed for how establishments may develop policies for managing collected units, from eligible donors, that later test reactive. FDA participants noted that there were no comments submitted to this section of the proposed rule when it was published in 2007, asked for a better understanding of the numbers involved, and said the issue would be taken under consideration.
Plasma for further manufacturing – An infrequent plasma donors is defined at § 630.3(e) as "a donor who has: (1) Not donated plasma by plasmapheresis or a co-collection of plasma with another blood component in the preceding 4 weeks; and (2) Not donated more than 12.0 liters of plasma (14.4 liters of plasma for donors weighing more than 175 pounds) in the past year," and it appears the definition will be helpful with collections of Concurrent Plasma when the FDA publishes guidance recommendations on the subject. § 630.25 describes exceptions from certain requirements for infrequent plasma donors not participating in immunization programs – medical history and physical exams, total protein, total plasma or serum protein and immunoglobulin composition, and review of certain records and data – such that variances under §640.120 will no longer be required for infrequent collection programs. The Committee has a long history of discussions with the FDA on plasma for further manufacture—plasma collected from whole blood donors utilizing manual techniques and/or automated collection technology and the need for complete flexibility in inventory management—and noted appreciation for indications in the Final Rule that a regulatory pathway is closer at hand.
At the same time the Committee noted a missed opportunity when updating § 640.69 General Requirements (for Source Plasma) to harmonize US plasma regulations with those of the European Union. § 640.69 was included in the Federal Register Notice due to the addition of (e) and (f). However, troublesome language in existing (b) was not addressed, leaving the phrase "immediately after filling" as the time by which collected plasma must be placed at -20 C or colder. Blood centers in the US with source plasma licenses are told that 2 hours is the operational standard set by the FDA to meet the requirement for "immediately after filling." In the EU, plasma for further manufacturing into labile products can go into the freezer up to 24 hours after collection. Plasma fractionators – responsible for manufacturing finished products to meet standards of safety, purity and potency – do not require that collected plasma be placed in the freezer "immediately after filling."
As this is an important issue for blood centers that operate collection sites distant from the manufacturing site, the Committee asked the FDA what route is available to an EU-like requirement for placing collected source plasma into freezers after collection. A brief discussion of the issue ensued. FDA participants noted that the requirement in the CFR is for "immediately" because of concerns for plasma protein levels in the final product and "within 24 hours" does not seem likely to meet the definition. Committee participants suggested that 1) a more scientific-based requirement should be used and 2) manufacturers of final product should be a part of the discussion.
As early as 2010, when a two day public work shop was convened in July of that year, the FDA announced its intention to end enforcement discretion of regulations where Laboratory Developed Tests (LDTs) are concerned. The FDA has continued to make known its framework for oversight, published guidance documents, and held more meetings for members of industry and the public. Members of the Committee have actively participated in opportunities to present concerns about the changes proposed by the FDA. Comments were submitted to two draft guidance documents, Framework for Regulatory Oversight of Laboratory Developed Tests and Notification and Medical Device Reporting for Laboratory Developed Tests. Following the comment period, the Center for Devices and Radiological Health invited organizations accredited/recognized by CMS for oversight of clinical laboratory compliance with CLIA to meet individually with the FDA team working on the framework for regulatory oversight of LDTs in order to better understand stakeholder concerns that had been expressed as duplicative and/or unnecessary oversight. AABB Standards, Accreditation, and Regulatory staff accepted an invitation to explain what AABB does to ensure compliance of a laboratory with CLIA, as well as additional requirements for accreditation with AABB.
The Liaison Committee remains concerned about many of the issues originally noted in the comments to the docket and brought them again to the attention of the FDA participants at the meeting. In addition to the items listed below, the committee members noted their continued concern of the far-reaching ramifications of these issues for transfusion medicine and that CDRH, as the lead center on this issue, may not have a full appreciation of all that is involved. The Committee impressed on the FDA representatives how important it is that CBER remain fully engaged in the guidance process.
A critical issue is that traditional immunohematology (hemagglutination testing—especially that using individual donor/patient sera or RBCs) be exempt from these rules. According to the guidance document, LDTs used in compatibility testing are categorized as High Risk. Comments to the docket and at the meeting with CDRH recommended that the appropriate category is Low Risk due to the level of oversight and inspection already in place (e.g., CLIA, AABB, CAP, and FDA).
Traditional LDTs are critical in the search for compatible blood and blood products for patients with complex antibody issues. The FDA 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. This distinction should not be made since both entities are necessary to provide compatible blood to patients 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."
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. It is not known whether FDA oversight of molecular testing—primarily sequencing using well validated platforms and methods—will stifle innovation, and this remains a concern. Generating highly precise data about rare sequences will be difficult in any pre- or postmarketing study.
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.
FDA participants noted that the FDA has received many strong comments about the draft recommendations and the agency's plans for oversight. There are many proponents for and against FDA enforcement. FDA (CDRH and CBER) are reviewing, carefully, all input and working toward final recommendations. There is concern about disrupting transfusion practice and that is being taken into consideration. FDA does believe they can manage oversight without stifling innovation.
Revised Recommendations for Reducing the Risk of Human Immunodeficiency Virus Transmission by Blood and Blood Products, draft guidance – The Federal Register Notice that accompanied the draft guidance requested comments on signs and symptoms associated with HIV that would be most appropriate for inclusion in the donor education materials, as the draft guidance does not provide such a list. Below is an excerpt of the comments to this docket provided by the blood community in support of the work of the AABB Donor History Task Force:
"We continue to object to a recommendation that donors be provided with education materials that list…the signs and symptoms associated with HIV infection….," as stated in Section III. Recommendations. A. Donor Education Material and Donor History Questionnaire. 1., and strongly recommend that this not be included in the final guidance. These are nonspecific and insensitive for the intended purpose— identification of HIV infected donors— and largely redundant when donors are asked and required to be well on the day of donation.
Prior to the 1985 advent of HIV testing and the evolution of ever more sensitive and specific serological tests and nucleic acid amplification assays, this recommendation was eminently reasonable—there were few alternatives except this information and risk factor deferrals available to mitigate HIV risk. However, they are no longer relevant under the current testing regime.
The amendments to the Code of Federal Regulations included in the [May 2015] final rule require that the educational materials [630.10 (b)] provide "an explanation of the readily identifiable risk factors closely associated with exposure to the relevant transfusion-transmitted infection." Elsewhere, in the same section, is a clarification that HIV is the relevant transfusion-transmitted infection to which this requirement applies. The requirement in the Final Rule is for "risk factors" not "signs and symptoms" in the educational materials. The FDA-accepted AABB Donor Educational Materials do contain risk factors for HIV. Further, new 630.10(e) describes how to conduct the medical history interview with a requirement in (1)(iii) to capture any information the donor provides that would be "Signs and/or symptoms of a relevant transfusion-transmitted infection." As mentioned above, the AABB Donor History Questionnaire (DHQ) requires the donor to affirm feeling well and healthy. Additionally, a temperature must be recorded.
The Committee re-presented the concerns to the FDA and offered any clarifications that might be helpful. They reiterated that a continued recommendation to provide donors with signs and symptoms of HIV infection is obsolete, nonspecific, and no longer relevant under the current testing regime. Further, it is distracting in the face of a growing volume of more important information that donors should integrate before donation. FDA participants noted a shared concern that the Donor Educational Materials should be meaningful and that the guidance with final recommendations is being worked on.
Bacterial Detection Testing by Blood and Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion, draft guidance – In responding to this docket, AABB, guided in part by its Bacterial Contamination Work Group of the Transfusion Transmitted Diseases Committee, expressed concern with the Important Note the FDA placed in several locations within the draft guidance, including when discussing a pathway to 7 day platelets.
Currently, appropriately labeled bacterial detection devices and platelet storage containers for the extension of dating beyond day 5 are not available. The additional considerations to extend platelet dating beyond day 5 in this section may not be implemented until the availability of both:
Included in the submitted comments to the docket was a recommendation "that the requirement for a 'safety measure' claim be applied only to rapid/point of issue devices and those devices with analytic sensitivity equivalent to the currently approved device that has a 'safety measure' claim be allowed that claim by default. Flexibility in this area and the availability of multiple options will encourage adoption of secondary testing in the transfusion service." This recommendation was bolstered by the "[belief that] that the agency is attempting to address a known sensitivity issue with non-culture-based tests and should acknowledge that validated studies are not needed to prove the sensitivity of culture-based tests used to detect bacterial contamination in platelet products. In addition, we believe there is generally little incentive for the manufacturers to invest in this activity."
The Committee noted that Fenwal (Fresenius Kabi) and TerumoBCT have received approval for label updates to store certain apheresis platelet products for 7 days, provided that the products are labeled with a statement that it must be tested with a bacterial detection device cleared by FDA and labeled as a "safety measure." Committee participants reiterated concerns that manufacturers of culture-based tests would have no incentive to obtain a safety measure claim. In response to questions about the role of pathogen reduction technology, the Committee was told that FDA's current considerations are to include this technology throughout the next draft guidance. An additional discussion item was the use of "options" and "recommendations" for transfusion services that were contained in the first draft guidance. FDA participants said that a deliberative process was used and that the use of "options" was intentional.
Peter Marks, MD, PhD, Deputy Director, Office of the Center Director (OD), Center for Biologics Evaluation and Research (CBER)
Ginette Y. Michaud, MD, Deputy Director for Medical and Scientific Affairs, Office of Blood Research and Review (OBRR), CBER
Martin Ruta, PhD, JD, Regulatory Counsel, OBRR
Alan Williams, PhD, Associate Director for Regulatory Affairs, OBRR
Jennifer Scharpf, MPH, Associate Director for Policy and Communications, OBRR
Salim Haddad, MD, Senior Medical Officer, Division of Hematology Research and Review, OBRR
Paul D. Mintz, MD, Director, Division of Hematology Clinical Review, OBRR
Orieji Illoh, Deputy Director, Division of Blood Components and Devices (DBCD), OBRR
Richard McBride, MS, MT(ASCP)SBB, Chief, Blood and Plasma Branch, DBCD
Judy Ciaraldi, BS, MT(ASCP)SBB, CQA(ASQ), Consumer Safety Officer, Blood and Plasma Branch
J. Peyton Hobson, PhD, Deputy Director, Division of Emerging and Transfusion Transmitted Diseases (DETTD), OBRR
David Leiby, Chief, Product Review Branch, DETTD
Gilliam Conley, Director, Division of Inspections and Surveillance, Office of Compliance and Biologics Quality, CBER
Faye Vigue, Consumer Safety Officer, Chief, Division of Manufacturers Assistance and Training (DMAT), Office of Communication, Outreach and Development (OCOD), CBER
Cynthia Whitmarsh, MS, Regulatory Professional, DMAT, OCOD
Lynne Uhl, MD, President, AABB
Graham Sher, MD, Ph.D., Immediate Past-President, AABB
Miriam A. Markowitz, MS, CEO, AABB
M. Allene Carr-Greer, MT(ASCP)SBB, Director, Regulatory Affairs, AABB
Susan L. Stramer, Ph.D., Transfusion Transmitted Diseases Committee, AABB
Ruey Dempsey, JD, Advanced Medical Technology Association
Kathryn Waldman, BA, Ph.D., American Red Cross
Christine Zambricki, DNAP, CRNA, America's Blood Centers
Louis M. Katz, MD, America's Blood Centers
Susan Rossmann, MD, Ph.D., America's Blood Centers
Capt. Roland Fahie, MS, MT(ASCP)SBB, Armed Services Blood Program
Anne F. Eder, MD, Ph.D., College of American Pathologists
Sharon Carayiannis, Deputy Director, Regulatory Affairs, AABB
Arnold McKinnon, Volunteer Coordinator and Advocacy Specialist, Regulatory Affairs, AABB