2 August 2022

Outstanding Project Management Team: Adaptive Orthopedic Biologics for Highly Targeted Regeneration

The primary aim of this Joint Warfighter Medical Research Program (JWMRP) Department of Defense (DoD) project (“Adaptive Orthopedic Biologics for Highly Targeted Regeneration”, W81XWH-15-C-0028) was to support the product development of an orthopedic implant platform technology that allows biological variants of regenerative proteins to bind to the surface of orthopedic implants for several weeks. This enables the delivery of lower doses of biologics with prolonged retention at the injury site and drives tissue regeneration of large bone defects, spinal injury or disc degeneration, and craniomaxillofacial injuries, potentially allowing more Service Members to remain on active duty in their designated Military Occupational Specialty (MOS) post-injury.

Led by LTC (Ret) Luis Alvarez, PhD, the team was comprised of eleven government, industry, and academic organizations to include U.S. Army Medical Materiel Development Activity (USAMMDA), U.S. Army Medical Research Acquisition Activity (USAMRAA), Institute of Surgical Research (ISR), National Cancer Institute – Frederick, Akron Biotech, Generic Devices Consulting Inc., South Australian Health and Medical Research Institute (SAHMRI), Mayo Clinic, Theradaptive, Cleveland Clinic Foundation, and The Geneva Foundation. Through these invested partnerships, the team successfully accelerated a nascent DoD effort into a multi-modality treatment poised for clinical trials, receiving two FDA breakthrough device designations in late 2021 and again in early 2022.

Through this effort, the team has been able to translate these findings into products that will have military benefit and will realize a large return on DoD investment in an area that is not well represented by other research efforts. Treating segmental defects remains one of the top challenges facing military medicine and some of the costliest injuries to treat. As of December 2021, the percent of our total force with deployment limiting medical conditions was 7% (with an intended target rate of 6% or lower). Further, musculoskeletal injuries comprised approximately 70% of all combat wounds in recent conflicts, with a significant fraction of these involving open complex fractures of long bones. These types of fractures generally exceed the critical size defect limit and do not heal well, often forcing the patient to decide between limb salvage with reduced function, or amputation. Similarly, lower back pain due to degenerative disc disease is one of the top reasons for medical separation from service during peacetime. The definitive treatment for degenerative disc disease is fusion surgery which requires the generation of bone between vertebrae. The product developed by this team addresses our total force non-deployability, provides a reduction in healthcare costs, and provides a benefit to wounded warriors while redefining how clinicians treat these kinds of injuries.

Spanning the full product development lifecycle (bench, pre-clinical, and product manufacturing), this contract was overseen by a dedicated integrated product team (IPT) made up of product and program managers, researchers at various performance sites, regulatory consultants, and acquisition teams. This seasoned IPT was instrumental in an effort that successfully stayed on schedule and under budget while navigating multiple levels of regulatory hurdles. Not only did our team navigate multiple Institutional Animal Care and Use Committee (IACUC) and Animal Care and Use Review Office (ACURO) approvals for both Good Lab Practices (GLP) and non-GLP animal studies, but also complied with Good Manufacturing Practice (GMP) regulations for all protein manufacturing to support future Food and Drug Administration (FDA) submissions which ultimately led to our breakthrough designations. Utilizing superior agile program management methodology, the program was continuously de-risked through bi-weekly IPT discussions, weekly team meetings with all team leads, and in-person annual product reviews with government leadership.

To ensure a successful on-time and on-budget outcome, the program management team identified project constraints and assumptions, developed a change control process, a quality management process, and a strong communication matrix to ensure full stakeholder engagement. This included the successful negotiation, execution, and management of over twelve agreements (i.e. Cooperative Research and Development Agreements (CRADA), subcontracts, vendors, and consultants) during the life of the project. The program management plan that was developed for this contract proactively addressed the mitigation of risks at all levels by developing a robust risk log that identified risk symptoms, triggers, along with detailed mitigation plans. Throughout the life of the project, issue summary reports were also used to effectively communicate potential schedule or budget impacts and changes to the integrated master schedule or scope of work. The team employed a fail-forward approach in which lessons learned were carried forward to successfully advance and navigate out-year milestones.

Furthering the success of the project, continual engagement of both patient and clinician from the design and intended use perspective ensured accelerated product development and end-user acceptance. This full user and recipient engagement methodology ultimately led to a therapeutic requiring minimal adjustment as the TRL/MRLs matured thus reducing development cost and commercial risk.

It should be noted that this was work was successfully driven to a final product as a result of the team’s decade-long dedication, perseverance, and ability to advance a medically relevant initiative, leveraging early DoD investments in basic science (this project originated through a CDMRP PRORP Career Development Award to LTC Alvarez in 2010).

A special thank you to all of the team members who made this research possible:

Luis Alvarez, Theradaptive, Inc. and US Army
David Stewart, Theradaptive, Inc.
John Greenbaum, GDCI Consulting, Inc.
Barry Sayer, USAMRAA
John Getz, USAMMDA
Jennifer Ojeda, USAMMDA
Patricia Henry, USAMMDA
Nicole Enman, USAMMDA
Judi Sgambato, USAMMDA
Eva Lai, TATRC
Melinda Eaton, USAMMDA
Scott Garrond, USAMMDA
Stephanie Mizell, USAMMDA
David Saunders, USAMMDA
Lloyd Rose, USAMMDA
Linzie Wagner, The Geneva Foundation
Marjorie Osmer, The Geneva Foundation
George Klarmann, The Geneva Foundation
Elise Huszar, The Geneva Foundation
Miranda Pelky, The Geneva Foundation
Josh Wenke, U.S. Institute of Surgical Research
Stefanie Shiels, U.S. Institute of Surgical Research
Claudia Zylberberg, Akron Biotech
George Muschler, Cleveland Clinic Foundation
Michael Yaszemski, Mayo Clinic
Kathy Berst, DHA (then USAMMDA)
Tim Kuchel, SAHMRI
Susan Porter, SAHMRI
Todd Heil, Theradaptive, Inc.
Anita Gugel, Theradaptive, Inc.
Hyeon Park, Theradaptive, Inc.