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Collaborate in the development of a standardized Factor XIa reference reagent for Immune Globulin Thrombogenicity Testing

Description: Factor XIa content in plasma-derived immunoglobulin products has recently been shown by FDA scientists to be related to an increased risk of thromogenicity in product recipients. FDA scientists will collaborate with the WHO Expert Committee on Biological Standardization (ECBS) to develop and characterize the 1st International Reference Reagent for Factor XIa, and, to conduct thrombogenicity assay harmonization studies with the European Medicines Agency (EMA) and National Institute for Biological Standards and Control (NIBSC).

FY 2021 Updates

Milestone Description	Milestone Date	Milestone Status	Milestone Completion Date
No update to report this quarter	Quarter 1	Completed	Quarter 1
This report covers the progress on the international collaborative study on measurement of FXIa activity in immune globulin products by thrombin generation assay. The last dataset from the participating laboratories has been received in March of 2021, concluding the data collection stage of the study. CBER has finished the preliminary analysis of data from all participants and is currently conducting the statistical analysis for the final study report. The report completion is expected by September, 2021.	Quarter 2	Completed	Quarter 2
No update to report this quarter	Quarter 3	Completed	Quarter 3
No update to report this quarter	Quarter 4	Completed	Quarter 4

FY 2020 Updates

Milestone Description	Milestone Date	Milestone Status	Milestone Completion Date
No update to report this quarter	Quarter 1	Completed	Quarter 1
An international collaborative laboratory exercise of the Study Group on Thrombin Generation Tests (SG-TGT) of the Global Working Group (GWG) on Immune Globulin Thrombogenicity Assays has been organized by the FDA/CBER in collaboration with the NIBSC, UK. One third of the participants, including the FDA laboratory, have completed the study and returned their data for analysis. The remaining participants expect completion of the study over the next several months. The FDA/CBER laboratory is now conducting preliminary review of the results and developing approaches for statistical analysis of data. The preliminary report of this collaborative study will be available in the third quarter of 2020.	Quarter 2	Completed	Quarter 2
An international collaborative laboratory exercise of the Study Group on Thrombin Generation Tests (SG-TGT) of the Global Working Group (GWG) on Immune Globulin Thrombogenicity Assays has been successfully completed by all study participants. Six laboratories provided the results and another three laboratories plan to submit the results in November, 2020. The FDA/CBER laboratory has developed the software for data analysis and is now conducting analysis of submitted data.	Quarter 3	Completed	Quarter 3
No update to report this quarter.	Quarter 4	Completed	Quarter 4

FY 2019 Updates

Milestone Description	Milestone Date	Milestone Status	Milestone Completion Date
FDA, in collaboration with the NIBSC, UK, designed a collaborative study protocol for the Study Group for Thrombin Generation Tests (SG-TGT); a research collaboration between stakeholders in regulation, standardization, and manufacturing tasked with creating harmonized assay protocols for using TGT to assess FXIa procoagulant activity in IgG products. The primary goal of the SG-TGT collaborative study is to produce a harmonized TGT protocol specifically for FXIa activity testing in an IgG quality control laboratory. Participants will collaborate to determine best practices and reference materials for IgG testing. The SG-TGT study report will be aggregated into a harmonized protocol to be verified in a large multicenter study to be organized by the NIBSC in 2019. The harmonized TGT protocol is seeking to: 1. resolve technical issues produced by specific analytical variables; 2. unify assay performance and reduce center-to-center variability; 3. serve as templates for assay performance by participant agencies and manufacturers; 4. stimulate future collaborative studies among relevant stakeholders; and 5. facilitate an agreed upon specification that reflects the clinical safety of IgG products. The finalized protocol will be submitted to study participants in Spring of 2019 along with the samples prepared for this collaborative study. These samples were manufactured by the NIBSC team from the IgG materials and assay reagents sourced from the participating stakeholders.	Quarter 1	Completed	Quarter 1
No update to report this quarter.	Quarter 2	Completed	Quarter 2
FDA finalized the protocol for a collaborative study on Thrombin Generation Tests for Procoagulant Activity and worked with the NIBSC, UK on two preparation of two freeze-dried panels of immune globulin.	Quarter 3	Completed	Quarter 3
An international collaborative laboratory study for the Study Group on Thrombin Generation Tests (SG-TGT) is underway. The results of this collaborative study, organized by the Global Working Group (GWG) on Immune Globulin Thrombogenicity Assays, will be available in early 2020.	Quarter 4	Completed	Quarter 4

FY 2018 Updates

Milestone Description	Milestone Date	Milestone Status	Milestone Completion Date
No update to report this quarter	Quarter 1	Completed	Quarter 1
No update to report this quarter	Quarter 2	Completed	Quarter 2
US FDA participated in two meetings of the Global Working Group (GWG) on Immune Globulin Thrombogenicity Assays. FDA scientists were selected to chair a GWG’s study group on the harmonization of Thrombin Generation Tests, and are currently working with the National Institute of Biological Standards and Control (NIBSC), UK to design a collaborative study on Thrombin Generation Test procedures. The collaborative study will compare and harmonize commercial and in-house Thrombin Generation Tests using a specially prepared NIBSC reference panel comprised of representative licensed Immune Globulin products donated by the manufacturers. The participants in the upcoming Thrombin Generation study will represent the Immune Globulin stakeholders, including Immune Globulin product manufacturers, in vitro diagnostic product (IVD) manufacturers, international regulatory agencies, and the United States Pharmacopeia (USP).	Quarter 3	Completed	Quarter 3
No update to report this quarter	Quarter 4	Completed	Quarter 4

FY 2017 Updates

Milestone Description	Milestone Date	Milestone Status	Milestone Completion Date
No update to report this quarter	Quarter 1	Completed	Quarter 1
FDA is currently reviewing the summary for the Immunoglobulin Stakeholders Forum that was held September 7-8, 2016. The summary was prepared on behalf of the Global Working Group for the Measurement of Procoagulant Activity of Immunoglobulins. FDA is also working with the National Institute for Biological Standards and Control (NIBSC, United Kingdom) on the design of collaborative harmonization studies.	Quarter 2	Completed	Quarter 2
FDA participates in the Global Working Group for the Measurement of Procoagulant Activity of Immunoglobulins (IG) formed in collaboration with the European Directorate for the Quality of Medicines (EDQM), National Institute for Biological Standards and Control (NIBSC, UK), and United States Pharmacopeia (USP) to have industry-wide harmonized assays for detection of thrombogenic impurities and thus prevent distribution of unsafe Immunoglobulin (IG) products to patients. At the recommendation of the Immunoglobulin Stakeholders Forum that was held September 7-8, 2016, three smaller study groups (SG) were recently formed to address issues related to specific assays for procoagulant activity in IG products: (1) Thrombin Generation Tests (SG-TGT) chaired by Dr. Mikhail Ovanesov from CBER, FDA, (2) FXIa functional assays (SG-FXIa) chaired by Dr. Johannes Dodt from Paul-Ehrlich-Institut, Germany, and (3) Non-activated partial thromboplastin time assays (SG-NAPTT) chaired by Dr. Kevin Carrick from USP. The SG programs will include small collaborative laboratory investigations, and the results will be used to formulate harmonized assay protocols. The harmonized protocols will be verified further in a large multicenter study to be announced in 2018.	Quarter 3	Completed	Quarter 3
No update to report this quarter	Quarter 4	Completed	Quarter 4

FY 2016 Updates

Milestone Description	Milestone Date	Milestone Status	Milestone Completion Date
FDA/CBER and the European regulatory agencies are working together on the establishment of a Global Working Group on Measurement of Procoagulant Activity in Immune Globulins. The collaborative Working Group is currently discussing a stake holder meeting with the Immune Globulin manufacturers and assay manufacturers to describe the state of the art in procoagulant activity testing. FDA is also working with the NIBSC, UK on the plans for collaborative studies and the utilization of the International Reference Panel for Procoagulant Immune Globulins.	Quarter 1	Completed	Quarter 1
The Global Working Group has agreed to hold a stakeholder meeting on the testing of pro-coagulant activity in immune globulins. Product and assay manufacturers, European regulatory agencies and the US FDA are now discussing agenda, time and place of the upcoming meeting.	Quarter 2	Completed	Quarter 2
No update to report this quarter.	Quarter 3	Completed	Quarter 3
The Global Working Group on Immune Globulin Thrombogenicity Assays collaborated with the Plasma Protein Therapeutics Association (PPTA) to organize a stakeholder meeting on the testing of pro-coagulant activity in immune globulins in Washington, DC in September, 2016. During the meeting, Immune Globulin product manufacturers, in vitro diagnostic products (IVD) manufacturers, European regulatory agencies, United States Pharmacopeial (USP) and the United States Food and Drug Administration (FDA) agreed on the urgent need for collaborative studies to harmonize assay procedures. Scientists from the National Institute of Biological Standards and Control (NIBSC), UK and the US FDA started working on the design of these harmonization studies.	Quarter 4	Completed	Quarter 4

FY 2015 Updates

Milestone Description	Milestone Date	Milestone Status	Milestone Completion Date
CBER continues collaboration with immune globulin manufacturers and international regulatory agencies on the laboratory methodologies that can detect and prevent distribution of potentially thrombogenic immune globulin products. Our efforts are presently focused on the harmonization of procoagulant activity measurements conducted by quality control laboratories. In November of 2014, CBER participated in the United States Pharmacopeia’s Expert Committee Meeting to discuss upcoming collaborative studies of inter- and intra-laboratory differences. A questionnaire was prepared to survey the current practices for procoagulant activity methods carried out for immunoglobulin products. The results of this survey will be used by the UK’s NIBSC to manufacture a panel of immune globulin samples with known procoagulant activity. CBER will participate in the evaluation of these samples as soon as they become available.	Quarter 1	Completed	Quarter 1
In March of 2015 CBER participated in several meetings with scientists from the European Medicines Agency, National Institute for Biological Standards and Control (NIBSC, United Kingdom) and the United States Pharmacopeia’s Expert Committee to discuss technical difficulties related to implementation of the 1st WHO International Standard for activated coagulation Factor XI (FXIa, NIBSC code 13/100). A consensus was reached that further research is needed to compare and harmonize different methods because the International Standard and multiple licensed immune globulin products have different compositions, and their effects on the assays may be different. Several international laboratory assay harmonization studies are now confirmed for 2015 and 2016. In preparation for these studies, CBER scientists are currently evaluating possible impacts of an assay reagent corn trypsin inhibitor and an immune globulin impurity apolipoprotein H on the candidate thrombogenicity assays. The results of CBER studies will support development of a standardized Immune Globulin Thrombogenicity Testing.	Quarter 2	Completed	Quarter 2
FDA participated in preparation of a draft proposal for the Joint USP-NIBSC-FDA project on Investigation on Assays for Procoagulant Activity of Immunoglobulin Products. The first draft of the project proposal was issued in April 2014. The collaborative project goals include the development of recommendations for refined and standardized testing procedures, validation of the testing recommendations, verification of procedures on a panel of immunoglobulin products, and will culminate in the publication of findings in a peer review journal. It is envisioned that the project will involve three multicenter collaborative laboratory studies.	Quarter 3	Completed	Quarter 3
Measurement of procoagulant activity in immune globulin products is still an unresolved issue recognized by FDA, product manufacturers and international regulatory agencies. FDA/CBER has been working with the European regulatory agencies to harmonize the two previously established initiatives, a US-led CBER/USP/NIBSC study and the European study sponsored by the Group 6B of the European Pharmacopoeia. In October of 2015, the parties agreed to establish a Global Working Group on Measurement of Procoagulant Activity in Immune Globulins with membership from each organization. The collaborative Working Group proposes to develop, refine and standardize testing procedures, evaluate optimized procedures in a small collaborative study, and verify these procedures on a panel of immune globulin products in a large collaborative study. The Working Group will work with the Expert Committee on Biological Standardization (ECBS) to inform the WHO on the need to establish new reference preparations such as the International Reference Panel for Procoagulant Immune Globulins. In addition, OBRR participated in the October 2015 meeting of the WHO Expert Committee on Biological Standardization (ECBS), where the WHO Prequalification Program for IVDs was discussed. Details of the meeting are not available at this time.	Quarter 4	Completed	Quarter 4

FY 2014 Updates

Milestone Description	Milestone Date	Milestone Status	Milestone Completion Date
CBER and the National Institute for Biological Standards and Control (NIBSC) (UK) are currently discussing design of the International Study CS504 to establish the 1st International Standard (IS) for Activated Coagulation Factor XI (FXIa), Human. The study is led by the NIBSC with the participation of CBER laboratory. The NIBSC study samples have been received by CBER laboratory on January 15, 2014. The primary goal of the collaborative study is to value assign the functional activity of the proposed 1st IS for FXIa, relative to the Reference Reagent for FXIa (NIBSC code 11/236). The secondary goal of the study is to explore the performance of the FXIa candidates and their use in the assessment of procoagulant activity by a variety of in-house and commercial methods used for release of Immune Globulin (IG), Intravenous or Subcutaneous products. The third goal of the collaborative study is specific to the CBER laboratory. We will evaluate the potency results, variability, and limits of detection of CBER’s investigational methods relative to other common tests and laboratories.	Quarter 1	Completed	Quarter 1
1) Completed participation in the NIBSC study to develop the 1st WHO IS for FXIa, NIBSC 13/100; a preliminary report was issued by the NIBSC on 4 April 2014 to the participants for review. 2) Data were presented at two regulatory meetings, the 5 February 2014 FDA-EMA-HC Blood Cluster meeting and 18 March 2014 teleconference with the EMA-EDQM Meeting on Establishment of Common Test for Procoagulant Activity of Immunoglobulins. CBER presented data on the commutability of the NIBSC FXIa standard between 9 methods used for procoagulant activity testing. 3) OBRR started preliminary non-binding discussions with the USP on a collaborative NIBSC-USP-FDA-industry multi-laboratory study on the harmonization of IG thrombogenicity testing.	Quarter 2	Completed	Quarter 2
Development of the immune globulin procoagulant activity methods and the WHO 1st International Standard for coagulation FXIa were discussed during the 18 June 2014 FDA/EMA/Health Canada (HC) Blood Cluster Teleconference. EMA laboratories will be invited to participate in the future multi-laboratory studies on the commutability of the WHO FXIa standard.	Quarter 3	Completed	Quarter 3
CBER reviewed the NIBSC report presented for ECBS approval entitled "WHO/BS/2014.2245 Value Assignment of the Candidate 1st Internationnal Standard for Activated Blood Coagulation Factor XI (FXIa), Human, NIBSC Code 13/100." CBER supports the establishment of the 1st International standard for FXIa.	Quarter 4	Completed	Quarter 4

FY 2013 Updates

Milestone Description	Milestone Date	Milestone Status	Milestone Completion Date
Reviewing final report on the collaborative study on the 1st international reference reagent for activated Factor XI; discussing the plans for the FXIa multi-assay performance study.	Quarter 1	Completed	Quarter 1
Waiting for National Institute for Biological Standards and Control (NIBSC) study protocol to review.	Quarter 2	Completed	Quarter 2
Waiting for NIBSC study protocol to review.	Quarter 3	Completed	Quarter 3
Reviewed the “Final report on the evaluation of the WHO Reference Reagent (RR) for Activated Blood Coagulation Factor XI (FXIa), Human” from the NIBSC which was presented to the Expert Committee on Biological Standardization (ECBS) in Geneva, October 21-25, 2013. Reviewed ECBS 2013 document, “Proposal for the 1st WHO International Standard (IS) for Activated Coagulation Factor XI (FXIa)” also from the NIBSC. This will replace the Reference Reagent discussed above. OBRR decided to support the establishment of this new WHO standard. A principal NIBSC scientist on the 1st IS FXIa standard study, Dr. Elaine Gray, will be visiting OBRR on November 6, 2013 to specifically discuss the design of the study.	Quarter 4	Completed	Quarter 4

Key Projects Legend

Milestone Status	Definition
Not Yet Started	Work for specific milestone has not yet been started.
Completed	Milestone and/or overall project is completed.
On Track	Milestone - On track for completion by milestone deadline. Quarter status - Project is on track for completion based on overall milestone status.
On Hold	Milestone - On hold, but deadline for completion has not passed. Quarter status - Project is on hold, based on overall milestone status.
Delayed	Milestone - Delayed as it has not been completed and deadline has passed. Quarter status - Project is delayed based on overall milestone status.