Therapeutic Monitoring of Hemophilia A

Presentations & Discussions:

Dr. Susan Shurin, NHLBI Acting Director, welcomed all participants and Drs. Keith Hoots, Donna Di Michele and Ken Mann outlined the goals of the meeting and charge to the working group members. During the open session working group members and interested parties from academia, government and industry listened to presentations and participated in discussions on current methods used to monitor hemophilia treatment, future needs for monitoring therapy and the challenges to global assay implementation. The first day program was divided into three Sessions with presentations in the following areas:

• Biology Informing Global Assay Technology
• Assays Currently Used for Monitoring HA Therapeutics: Utility and Limitations
  (of current FVIII products, bypassing agents, long acting/increased potency products, gene therapy products, potential for individualized therapy)
• Current Status of Thrombin Generation Assay (TGA) in Therapeutic Monitoring (hemophilia A with no inhibitors & with inhibitors)
• Current Status of Thromboelastography (TEG) in Therapeutic Monitoring (hemophilia A with no inhibitors & with inhibitors)
• Global Assay Standardization (TGA & TEG)
• Global Assay Technology - Further Considerations (alternative approaches & microfluidics)
• Adaptability of Global Assays to Clinical Trials (perspective of clinical investigator, clinical laboratory, industry & regulators)
• Adaptability of Global Assays to the Clinical Care Setting (TGA, TEG and applicability to clinical scoring)

Dr. Ken Mann and Session Chairs, Drs. Steve Pipe, Diane Nugent & Nigel Key provided their summary of the first day discussions to all participants on the morning of the second day. The meeting identified the need to define the bleeding phenotype and clinical response to therapeutic intervention, address the ways that assays are vetted and standardized and determine how to implement the assays for clinical studies. They provided the following list of characteristics needed in an assay to meet future needs:

• Ability to capture and characterize phenotypic variability
• Clinically useful in both diagnostic and therapeutic monitoring across a broad hemostatic range
• Ability to characterization native plasma-derived and bioengineered factor products as well as novel therapeutics
• Predictive of clinical outcome endpoints
• Established reference ranges
• Ability to be validated and subsequently implemented within existing clinical trials
• Endorsed by regulatory agencies

They recommended a framework to move the TGA and TEG assays forward that would consist of three working sub-committees (Panels) and an Executive Chair to continue the work begun by this Global Assay Working Group meeting. Because this is of international interest the 1) Clinical Outcome Endpoints, 2) Assay/Technical and 3) Clinical Trial Implementation panels would each have one US and one EU co-chair. The panel co-chairs would select additional members, determine goals, prepare a budget and set timelines for the work over the ensuing year. Dr. Nigel Key agreed to be the Executive Chair and oversee the three panels. Drs. Guy Young and Flora Peyvandi agreed to be the co-chairs for Clinical Outcome Endpoints; Drs. Kathleen Brummel-Ziedins and Benny Sorensen will be the co-chairs for Assay/Technical and Drs. Diane Nugent and Claude Negrier will be the co-chairs for the Clinical Trial Implementation. The industry representatives present agreed to provide support for the Panel activities through a nonprofit organization. A meeting of all industry-stakeholders, Drs. Mann and Key, and the Panel Co-chairs will be held in conjunction with the upcoming International Society on Thrombosis & Haemostasis (ISTH) meeting in Japan to discuss the details of the arrangement.

Closed Session:

During the closed session the working group members determined the focus should include both hemophilia A and B, but not be immediately expanded to other hemostatic or thrombotic disorders. They refined the goals for the three panels:

1. Clinical Outcome Endpoints Panel - Establish and define consensus clinical outcome parameters to be used in assay validation studies and subsequent therapeutic clinical trials. Outcome endpoints would build upon the output of the Definitions Project Group of the FVIII/IX Subcommittee of the ISTH but would be specific to the above-stated goal. A secondary aim of this group would be to ascertain clinical endpoints that would define baseline clinical bleeding phenotype in hemophilia and could be used to validate standardized global assays in diagnostic and tailored therapeutic trials.
2. Assay/Technical Panel - Establish consensus pre-analytical and analytical test conditions by which both assays can be standardized across laboratories and satisfy harmonized regulatory requirements prior to use in validation studies and therapeutic clinical studies/trials.
3. Clinical Trial Implementation Panel - Determine how standardized global assays and consensus outcome endpoints can be integrated into pre- and post-licensure clinical trials initially for assay validation and subsequently for ascertainment of product safety and efficacy.

The Panel co-chairs agreed to plan initial meetings at the July 2011 ISTH meeting, constitute the membership of their respective panels and interact with other individuals or groups working on these issues. A writing committee was formed from among the panel co-chairs with the goal of drafting a report summarizing the outcomes of the meeting for publication in a peer-reviewed journal. The paper will explain the reasons for creating the panels and their working goals.

Conclusions:

• The planning and conducting of the Panels projects will be supported by industry through a nonprofit organization.
• Until an arrangement is made for a nonprofit organization to host its activities, NHLBI and/or FDA could assist initial efforts by providing the Panels with access to teleconference technology.
• There should be continued interaction with NHLBI and the FDA as the Panels move forward.
• The NHLBI biorepository may provide a valuable resource for Panel projects.
• The outcome from their endeavors could result in hypothesis-driven protocols that qualify for individual NIH grants.
• The NHLBI could convene a follow-up working group meeting in 2012 to evaluate progress of the Panels and determine next steps.

Working Group Members:

Kenneth G. Mann Ph.D., Working Group Chair, University of Vermont
Steve Pipe, M.D., Session 1 Chair, University of Michigan Health System
Diane Nugent, M.D., Session 2 Chair, Children’s Hospital of Orange County
Nigel Key, M.D., Session 3 Chair, University of North Carolina at Chapel Hill

Katheleen Brummel-Ziedins, Ph.D., University of Vermont
Jorge DiPaola, M.D., University of Colorado Denver
Elaine Gray, Ph.D., National Instiute for Biological Standards and Control, UK
Nisha Jain, M.D., Center for Biologics Evaluation & Research, FDA
David Lillicrap, Ph.D., Queen’s University, Ontario, Canada
Marilyn Manco-Johnson, Ph.D., University of Colorado Denver
Claude Négrier, M.D., Head, Hôpital Edouard Herriot, France
Mikhail Ovanesov, Ph.D., Center for Biologics Evaluation & Research, FDA
Flora Peyvandi, M.D., University of Milan, Milan, Italy
Benny Sorensen, M.D., Guy’s and St. Thomas’s National Health Service Foundation, UK
Guy Young, M.D., University of Southern California Keck School of Medicine, Los Angeles, CA

NHLBI Staff Members:

Donna Di Michele, M.D., Deputy Director, DBDR; Acting Chief, Thrombosis and Hemostasis Branch
Keith Hoots, M.D., Director, DBDR
Rebecca Link, Ph.D., Program Director, Thrombosis and Hemostasis Branch, DBDR

Last Updated September 2011