Therapeutic Hypothermia

The experimental use of hypothermia in people with nervous system trauma came about after years of laboratory research conducted by W. Dalton Dietrich, Ph.D., and his colleagues.  Their work, beginning in the 1980s, showed that cooling the body temperature a couple of degrees resulted in improved recovery of walking in paralyzed rats.  Currently, they continue their work to gain a better understanding of the biochemical, histological and physiological effects of hypothermia.
 
It took some years to begin testing this therapy in people partly because reliable methods to cool patients still needed to be developed.  By the year 2000, several companies had developed devices to control a patient’s temperature.  An initial goal of using cooling devices was to counteract fever in patients with stroke, heart attacks, head trauma and spinal cord injury. Fever is common in these patients and studies by various investigators, including Helen Bramlett, Ph.D., at The Miami Project, report that small increases in body temperature can worsen neurological outcome.

Today’s very sophisticated cooling devices now allow clinicians to accurately record and manipulate a patient’s body temperature.  With this degree of control, it appears possible to safely cool injured patients and, with further study, potentially give them a chance for better neurological recovery.

CLINICAL TRIALS INITIATIVE UPDATE

Schwann Cell IND Progress

Investigational New Drug Process

The Food and Drug Administration (FDA) may seem like an insurmountable hurdle to getting drugs, devices, and cellular therapies approved for treating many devastating diseases/conditions that the public faces, such as spinal cord injury (SCI) and traumatic brain injury (TBI). However, the mission of the FDA is to protect public health. To do this in a reliable and standardized manner, a step-wise process has been developed to take potential therapies from “discovery-to-development-to-market”. Basic science is the discovery phase. When an intervention shows promise in the laboratory, and the decision is made to develop and investigate its potential in humans, the pre-clinical or non-clinical phase begins. This early development phase is done in animals to demonstrate that the intended therapy is reasonably safe before proceeding with small scale human clinical studies. Depending on the complexity of the target disease/condition and the intended drug/device or biologic therapy, the pre-clinical phase can take 2-5 years. A critical part of this time involves the creation of relevant disease/condition models in animals. To determine safety for use in humans, toxicology studies, dose and delivery studies, and, for cellular therapies, biodistribution (movement to different organs) and tumorigenicity (possibility of forming tumors) studies are conducted in animals. When safety has been established, an Investigation New Drug (IND) application is submitted to the FDA requesting approval to begin a phase I study in humans. Phase I studies enroll a very small number of research subjects (in the 10’s). The main goal (primary endpoint) is to determine safety. This is done by observing for adverse responses, monitoring for toxicity and in most situations also determining if the dose produces therapeutic activity. If the phase I study is successful, then a phase II study is proposed to the FDA. Phase II studies enroll more subjects (in the 100’s) and include a control (placebo) group for comparison. The primary endpoint is also safety (by determining short-term risks), but preliminary determinations of producing a beneficial effect (efficacy) are the secondary endpoint. The next step is to conduct a phase III study. Phase III studies involve a large number of research subjects (1000’s) and the primary endpoint is efficacy. These studies are also controlled (placebo group), randomized (subjects randomly assigned to either the drug/cell group or the placebo group), and blinded (the participants do not know which group they are assigned to). Phase III studies are considered “pivotal” because if they are successful a New Drug Application (NDA) can be submitted for final approval. However, if they are unsuccessful, the intervention can go no further in the process. It takes approximately 6-7 years to complete the development phases I-III studies and anywhere from 6 months to 2 years to obtain the approved NDA. Once the FDA approves the NDA for a particular drug/cell therapy, the intervention is then widely available to any individuals that qualify for it and it can be prescribed by physicians.

The Miami Project has been hard at work to move the Autologous Schwann Cell Transplantation therapy for SCI through the FDA process. It was only in December 2007 that we decided to transition from the discovery phase to the pre-clinical phase for this therapy. We have made tremendous accomplishments in just 2 short years. An important factor that facilitated the success and speed of all of those accomplishments was the hiring of Mr. Anil Lalwani, M.S., as the Project Manager. Mr. Lalwani has over 15 years of experience in the biotechnology field, including Good Manufacturing Practice (GMP), Good Laboratory Practice (GLP), Quality Systems Regulation (QSR), and FDA regulatory compliance. He is currently the Director of Biotechnology Resources at the University of Miami Miller School of Medicine and for the last year has dedicated 20% of his time to managing our Schwann cell therapy project. He also facilitated our pre-pre-IND discussion with the FDA and his experience and knowledge of regulatory affairs and project management has been essential to our navigation of the pre-clinical phase and will be even more critical as we prepare our IND application for submission to the FDA.

What is an IND? An IND can be considered a legal permit to test an unproven drug/cellular therapy in humans. This became federal law as a result of past unethical experimentation on humans (such as the Tuskegee Incident, Thalidomide Tragedy, World War II Nazi concentration camps). An IND application has the following three main components: 1) Animal pharmacology and toxicology studies; 2) Manufacturing and Controls information; 3) Clinical protocols and investigator information.

Under the guidance of Mr. Lalwani, we are deep in the process of our animal pharmacology and toxicology studies for the Schwann cell transplantation therapy. When we had our pre-pre-IND discussion with the FDA in August 2008, they stated specifically that they wanted to see data about toxicity, cell survival, migration of the cells to other body parts (biodistribution), and whether or not they formed tumors (tumorigenicity) in animals 6 months after the cells had been transplanted. We began these studies by utilizing our human Schwann cell product and transplanting it into rats. These studies require immunosuppression treatment, because the rat body recognizes human cells as foreign and tries to kill them, and have proven very difficult. We are currently conducting parallel experiments in which we are transplanting rat Schwann cells into rats. These studies do not require immunosuppression; however, we will need to demonstrate comparability between human and rat Schwann cells in our evaluations.

We have made quite a bit of progress regarding our manufacturing and control information. This includes very detailed information about the Chemistry, Manufacturing, and Control (CMC) of our human Schwann cell product. It requires a step-by-step description of how Schwann cells will be prepared in culture, after having been removed from a research subject in preparation for transplantation into the spinal cord injury site. Good Manufacturing Practices (GMP) must be followed and documented. To meet this requirement we have been working with colleagues at the University of Miami’s Wallace H. Coulter Center for Translational Research where there is a GMP facility. We have also developed several Master Batch Records and Standard Operating Procedures (SOPs) defining how Schwann cells will be harvested, separated from the nerve, expanded in culture, purified, and prepared for transplantation. A list of product release criteria will be established, which must be met each time Schwann cells are prepared for transplantation into a research subject.

We continue to make significant headway in preparing our clinical protocol and investigator information. We must provide a detailed outline of the investigation, taking into consideration differences between acute and chronic injury conditions. We must also include research subject screening criteria, safety exclusion criteria, a dosing plan and duration of the study, as well as a robust safety monitoring plan. Our remaining milestones are listed in the box below. It is imperative that we complete the toxicology and tumorigenicity experiments successfully in rodents. We will be holding a meeting with the External Advisory Board (EAB) for this study to seek their input on our pre-clinical data and clinical trial design. The EAB is a group of experts in SCI clinical trials who have no internal connection to The Miami Project (i.e. they are unbiased). Their guidance will be crucial to obtain prior to submitting our IND application. Proper trial design is very closely linked to the success of the trial. The last thing that the SCI field needs is another failed trial due to flawed design, so we are seeking as much input as possible ahead of time to prevent that from happening rather than rushing to the FDA with an ill-designed proposal. Once the clinical protocol is finalized, we will submit it to the University of Miami Miller School of Medicine Institutional Review Board (IRB) for human subject safety review. At the same time, we will arrange for a pre-IND consultation with the FDA. This will be our opportunity to ask the FDA any remaining questions prior to our submission of our IND application. After those questions are answered and we finalize our IND application, it will be submitted. It would not be out-of-the-ordinary for the IND application to be several thousand pages long; in fact, the IND application that Geron, Inc., submitted regarding stem cell use for acute SCI was 21,000 pages!

Overall, we are proud of the extensive progress we have made in only 2 years of pre-clinical development. The overriding factors guiding this process are safety and ethics. We thank the SCI community for their continued support as we continue to move forward!