TBI can be classified as mild, moderate, or severe based on specific criteria, such as the length of time an individual is unconscious following their injury. For example, an individual would meet the criteria for mild TBI if they suffered a loss of consciousness for 30 minutes or less. Similarly, an individual would meet the criteria for moderate TBI if they lost consciousness for more than 30 minutes and for severe TBI if they lost consciousness for more than 24 hours. (See table 1.) Early detection of injury is critical in the management of TBI patients. The diagnosis of moderate and severe TBI usually occurs in a timely manner due to the visible nature of the head injury, as well as the duration of symptoms, such as memory loss. Identification of mild TBI, also known as a concussion, can be challenging because there may be no visible head injury, and symptoms may be minimal and brief. In addition, in the combat theater, a mild TBI may not be identified if it occurs at the same time as other combat injuries that are more visible or life-threatening, such as orthopedic injuries or open wounds. Furthermore, some of the symptoms of mild TBI, which account for the majority of these injuries in the military, are similar to those associated with other conditions, such as PTSD. Individuals sustaining mild TBIs often report physical, cognitive, and emotional or behavioral symptoms referred to collectively as postconcussion symptoms. The most commonly reported postconcussion symptoms are headache, dizziness, decreased concentration, memory problems, irritability, fatigue, visual disturbances, sensitivity to noise, judgment problems, depression, and anxiety. Although the majority of individuals with mild TBI have symptoms that resolve within 1 month, some symptoms may persist for months to years following injury, potentially becoming permanent and causing disability. When these symptoms are persistent, they are often referred to as postconcussion syndrome or persistent postconcussion symptoms. PTSD can develop following exposure to life-threatening events, natural disasters, terrorist incidents, serious accidents, or violent personal assaults and may have a delayed onset, which is described as a clinically significant presentation of symptoms at least 6 months after exposure to trauma. Individuals diagnosed with PTSD may experience problems sleeping, maintaining relationships, and returning to their previous civilian lives. They may also suffer from other ailments, such as depression and substance abuse. PTSD is one of the most prevalent mental disorders arising from combat. for clinical purposes was “100 percent oxygen” instead of “near 100 percent oxygen” Hyperbaric Oxygen Therapy Indications, 12th Edition, 2008. However, the latest edition remained consistent that pressurization for clinical purposes should be 1.4 ATA or higher. FDA approves drugs and approves/clears devices for specific indications (diseases or medical conditions). However, it does not generally prevent healthcare practitioners’ use or prescribing of approved or cleared drugs/devices for indications for which the drugs/devices have not been approved or cleared. FDA has approved/cleared both the drug (oxygen) and the device (hyperbaric chamber) used in HBO therapy for certain medical uses, such as treating decompression sickness suffered by divers. As described by FDA officials, in order for HBOTBI or PTSD, sponsors would be required to submit a new marketing application or applications to support the new indications. Such submissions could be made in one of two ways: 1) the sponsor could submit one marketing application to FDA’s Center for Drug Evaluation and Research for both the drug and the device; or 2) the sponsor could submit a new drug application to FDA’s Center for Drug Evaluation and Research to add the new oxygen indication for the drug and a device premarket submission to FDA’s Center for Devices and Radiological Health to add the new indication for existing hyperbaric oxygen chambers. Typically before a marketing application submission, the sponsor meets with FDA to discuss the most appropriate investigational studies and the details of the regulatory process. If existing literature and data are available to address the scientific and technical questions, it might be possible to submit this information only, and new investigational studies might not be needed. If new investigational studies are needed, an investigational new drug (IND) application would be used. The IND would include information on both the drug and the device. The IND must also include a “proposed indication(s) for use” section that explains what the drug (or drug-device combination product) does and the clinical condition and population for which it is intended. The IND sponsor has overall responsibility for the conduct of clinical studies that would support use for the proposed indication. Typically, the investigational process is iterative and begins with early studies that focus on safety and dosing. Later studies generally focus on safety and effectiveness of the product. When the applicant completes the investigational studies and submits the necessary marketing application for review, FDA first determines whether the submission is complete and provides the information necessary for review. For example, the submission would provide information regarding the product description, proposed indications and potential clinical benefits, as well as the data needed to support approval or clearance, labeling, dose of the drug, and device instructions for use. FDA reviews the marketing application to determine such things as whether 1) the drug-device combination is safe and effective for its proposed use, which is answered, at least in part, by whether the benefits of the treatment outweigh its risks; 2) the proposed labeling meets the applicable regulatory requirements; 3) the methods used to manufacture the drug are adequate to preserve the drug’s identity, strength, quality, and purity; and 4) the methods used to maintain device functionality and performance are acceptable. If two marketing applications are used as in the second option noted above, FDA would generally issue the marketing authorizations concurrently when they are approved. Most of the 32 peer-reviewed, published articles that we identified examined the use of HBO therapy for treating TBI: 29 focused solely on TBI, 2 focused on both TBI and PTSD, and 1 focused solely on PTSD. The 32 articles we identified included 7 case reports, 10 literature reviews, and 15 articles on interventional studies or clinical trials. Case reports are collections of reports on the treatment of individual patients. Six of the seven case reports we reviewed found that the patients with TBI (mild, moderate, severe, or not specified) or PTSD improved after treatment. The remaining case report noted safety issues to consider when treating TBI patients with cranial fractures. Literature reviews use a search to identify studies on a specific clinical topic. Of the 10 literature reviews we identified, 1 concluded based on the articles it had identified that HBO therapy for treating TBI (severe and not specified), and all 3 concluded that the therapy is safe. The remaining 12 articles evaluated the effectiveness of HBO The 8 articles on mild TBI had differing conclusions on the effectiveness of HBO therapy, while the other 4 articles (two on severe TBI and two that did not specify severity) reported that this therapy was an effective treatment for these conditions. (For more detailed information about the articles and their conclusions, see appendix III for case reports, appendix IV for literature reviews, and appendix V for interventional studies or clinical trials.) The eight articles on interventional studies or clinical trials that were focused on treating mild TBI had different conclusions—six articles concluded that it was not effective and two concluded that it was. The six articles that concluded HBO Each of the three studies was affiliated with a branch of military service—Army, Navy, or Air Force. The remaining two articles were based on two studies conducted by researchers in Israel and the United States. The differences in the articles’ conclusions about the effectiveness of HBO therapy for treating mild TBI are based, in part, on methodological differences, as well as differences in researchers’ interpretations of the studies’ results. All of the DOD-funded studies were randomized, double- blinded, and included a sham control group in which participants received a procedure that is similar to the HBO For a sham control group in HBO therapy studies, some atmospheric pressure within the hyperbaric chamber is required for participants to perceive they are receiving treatment. However, there is no standard sham control group design for HBO therapy was not effective in treating mild TBI and related symptoms because participants in the sham control and treatment groups had similar outcomes. Although both groups of participants showed improvement, the authors concluded that the improvement was likely attributable to other factors, such as a placebo effect, and not to HBO DOD officials and researchers involved with the studies told us that they believe some improvements were due to factors, such as being away from home and everyday stress. therapy from this study. other researchers not affiliated with the DOD-funded studies have reported that hyperbaric treatments at 1.2 ATA (without increased oxygen levels), which was used as the sham treatment in one DOD-funded study, substantially increase the amount of dissolved oxygen in the blood and simultaneously induces other physiological changes. As a result, these other researchers stated that the sham control group’s treatment does not represent a true sham or placebo, and participants’ improvement shows that even a small increase in pressure is an effective treatment. In a published editorial, the researchers who conducted the DOD-funded study that used a sham control group with hyperbaric treatments at 1.2 ATA responded to these concerns by reporting that they recognize that the sham treatment may have caused physiologic effects from slight increases in oxygen, nitrogen, and direct pressure, as well as a variety of other effects. They added that the study was not designed to separate these effects, but rather to show a benefit of HBO therapy, and found it was not effective because the initial improvements identified after the treatments were not sustained. Nonetheless, DOD officials told us that there have been no studies completed on the long-term effects of the treatment, and such studies would help confirm whether the sham control groups’ improvements should be attributed to placebo effects or other factors. The remaining two (of eight) articles on mild TBI, which concluded that HBO The study conducted in the United States was not blinded and did not use a control group.