Authors: Bethany Kinseth Runge
Robert J. Spinner, MD
Michael J. Yaszemski
Anthony J. Windebank
Peripheral nerve injuries are common, and loss of peripheral nerve function results in paralysis, loss of sensation, and long-term pain. Peripheral nerves can regenerate, but do so effectively only for short distances. Currently, autologous nerve graft is still the clinical gold standard for repairing segmental nerve defects. Alternatives such as biological or synthetic materials have also been investigated and used. Three such materials, type I collagen nerve conduit (NeuraGen®), polyglycolic acid nerve conduit (Neurotube), and decellularized allograft nerve (Avance®), have obtained approval from the Food and Drug Administration (FDA) and undergone multicenter clinical trials.1-3
While mixed results have been reported, ultimately regeneration is inadequate to repair major defects because it cannot cross critical gaps produced by injuries or surgical interventions for tumor removal. Improved nerve repair strategies are greatly needed.
A Novel Device for Peripheral Nerve Repair
A collaborative research team at Mayo Clinic in Rochester, Minnesota, is currently investigating a novel biodegradable scaffold, the Mayo Clinic Nerve Scaffold 1 (MCNS1), to determine whether it could provide a better option for repairing peripheral nerve damage. The team has discovered that the pathway of getting the device to a first-in-human study has required a new way of thinking all around to address traditional translational barriers in order to get novel medical device to patients earlier.
The MCNS1 is a single tube (conduit) comprised of a novel (patented) biodegradable polymer (poly(caprolactone fumarate)) (PCLF), and will serve as a platform for an overall strategy to improve the treatment of peripheral nerve injuries. The scaffold is the first component of an intended combination device for nerve repair comprised of the scaffold seeded with autologous, peripheral nerve supporting myelinating cells (Schwann cells).
Intended to be an implantable investigational device, MCNS1 is a significant risk device and thus subject to FDA regulations. To investigate the safety of MCNS1 in human subjects, we began the steps for filing an investigator-initiated Investigational Device Exemption (IDE) with the FDA’s Center for Devices and Radiological Health (CDRH), and in our case, the construction of a laboratory that follows the FDA’s current Good Manufacturing Practices (cGMP) regulations (21CFR 820) to allow manufacturing onsite.
Assembling a Multi-disciplinary Team
A diverse, collaborative research team was assembled to accelerate translational activities. There was input by many individuals in and out of the clinic and research laboratory to complete required preclinical and regulatory activities. Our team consisted of neurologists, neurosurgeons, orthopaedic surgeons, chemical engineers, and polymer chemists. These individuals completed much of the discovery bench work and gathered the necessary preclinical data related to the chemical synthesis, device design, and mechanical and animal testing.
Our team also included those with legal, regulatory, and project management education, training, and experience. These individuals were responsible for supporting regulatory compliance, interfacing with internal and external regulatory agencies, and other general tasks related to the execution of the project.
We also relied on those outside our institution for input and to complete contract work on matters relating to biocompatibility testing, sterilization, and packaging. With this multi-disciplinary team, we were able to complete and submit a pre-submission package, essentially a reduced version of the IDE application, to the FDA.
The Early Feasibility Study (EFS) Pilot Program
Rather than the traditional IDE application being filed to conduct a firstin- human study to investigate the safety of MCNS1, an application for an investigator-initiated early feasibility study was submitted to the FDA under their 2013 Early Feasibility Study (EFS) pilot program.4-5
The EFS is a recent FDA initiative designed to promote earlier patient access to medical devices in the United States. Early feasibility studies provide investigators with the opportunity to initiate a clinical trial to evaluate a medical device on a smaller number of subjects before the device design is finalized, and offers the potential to begin a trial with less preclinical data than traditionally required. The program promotes communication between the investigator and regulators, and permits “just-in-time” (JIT) testing to allow for certain preclinical testing to be completed in parallel with an ongoing clinical study.
Patient safety is balanced by requiring investigators to outline enhanced risk mitigation strategies and patient protection measures through a Device Evaluation Strategy (DES). The steps that follow the completion of an early feasibility study depend on the clinical and device information obtained during the EFS.
In our case, an early feasibility study was the preferred method for capturing proof of principle and initial clinical safety data for many reasons, including the aforementioned unique features of the EFS program. A pre-submission package was submitted to the FDA content reviewers following initial informal communications with the EFS proponents.6 The pre-submission package was essentially a compact version of our full IDE submission.7 It included a summary of our device, study plan, DES, and a request for a pre-IDE meeting with the FDA. Next steps include submitting our full IDE for approval before we begin the study. Although taking this route has increased the front-end workload, the EFS program provided the opportunity to have more meaningful and interactive contact with the FDA before submitting the final IDE for approval to conduct our clinical trial.
Constructing a cGMP Laboratory for In-house Manufacturing
In support of the decision not to license the technology to an industry partner as is customary in academics, a small in-house laboratory following cGMP for manufacturing of biomedical products is currently being constructed. 8 Construction, validation, and commissioning are anticipated to be completed in early 2015. The facility will allow onsite chemical synthesis and device fabrication activities. Additionally, dedicated equipment and air handling will provide a controlled environment for manufacturing activities.
Within the facility, there will be an ISO 8, Class 100,000 room for chemical synthesis, and an ISO 7, Class 10,000 prefabricated clean room. The facility will follow an established Quality System of another cGMP laboratory at Mayo Clinic. With MCNS1, the polymer and device will be manufactured, sterilized, and packaged at this facility, with the final product ready for use in the clinical trial. The establishment of an in-house cGMP facility not only provides the infrastructure for manufacturing MCNS1, but can also support the development of other investigator-initiated biomedical devices.
A New Way of Thinking
By no means has the MCNS1 project followed the typical pathway to reach the patient (Figure 1). In using novel solutions to translational issues that are somewhat common in device development at academic medical centers, our goal is to get to first-in-human trials earlier.
Figure 1 The road from discovery to implementation
MCNS1 in particular has the potential to provide a different path and resources for translational research teams to investigate improved medical implant device strategies.
We would like to acknowledge the Department of Defense Armed Forces Institute of Regenerative Medicine (AFFIRM) and the Eugene and Marcia Applebaum Fund for Translational Research in Neuroscience Therapeutics for their generous funding.
Michael J. Yaszemski, MD, PhD, and Mayo Clinic have a financial interest in technology associated with this project. This technology is entitled “A Biodegradable Polymer Device for Surgical Implantation in Patients with Spinal Cord Injury,” Mayo Clinic case 2002-072. PCLF is patented by Mayo Clinic. No royalties have accrued to Mayo Clinic to date, but rights to receive future royalties exist.