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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 preclinical 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 preclinical 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.  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.

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.