Research Methods
The IHMF is Using the Latest Research Methods for Its Hyperbaric Medicine Research
The IHMF has received numerous requests for the FDA-Bayesian Device Guidance issued in 2010, as well as information to justify why the IHMF chose to use this methodology in our nationwide NBIRR-01 study on mild-moderate traumatic brain injury or PTSD. With the final adoption of this guidance in 2010, the FDA Devices division has clearly validated this methodology for acquiring Level 1 evidence FOR NEW MEDICAL DEVICES in the Evidence-based Medicine paradigm. The draft guidance was issued in 2006 and used by the devices industry for nearly 50% of all new device approvals over the last four years. If the Bayesian technique can be used for new devices, it can certainly be used for a new indication for an old device.
This statistical technique and research methodology clearly applies for all future indications or national coverage determinations sought for hyperbaric medicine. Hyperbaric chambers using oxygen have been in use for 74 years. All new hyperbaric chambers must have an FDA-clearance in order to be sold in the United States.
Those who contend that RCTs are required for approval of a new use of an already approved medical device that already has 13 broad indications are using out-of-date research thinking. Six of those current indications directly apply to the indication of traumatic brain injury. By insisting on a large RCT study for traumatic brain injury, they are delaying the study and use of hyperbaric oxygen under valid research methodology. This further delays the adoption of a therapy in a field for which there is no other biological repair treatment available. The effects of delaying effective biology brain injury treatment are devastating to these individuals’ lives. Delay carries great harm. There could be medical ethics and medical malpractice violations if these issues were fully examined.
In the case of the NBIRR study, hyperbaric medicine is being compared with the failed or ineffective therapies already in DoD medicine and VA general use, which have already been given to many LSU pilot research and NBIRR-01 study subjects. Many of those current treatments are Black Labeled by the FDA with side effects such as increased suicidality in those under 25, so hyperbaric oxygen therapy is far safer.
Those ineffective drug treatments have been adopted wholesale by DoD and VA medicine. They have not been subjected to randomized-controlled studies being required of HBOT 1.5 before being adopted. None of them are FDA approved for treating traumatic brain injury. The waste of taxpayer dollars on ineffective treatments is twice as much on a per year basis in this population as the one-time cost of treating war veterans with TBI or PSTD with HBOT 1.5. That does not count the savings in disability payments, social safety network costs, or lost future tax revenue!
Thus the written contentions by the Army Surgeon General that HBOT is more expensive than current treatments, or more labor intensive than warehousing nearly an entire division of wounded warriors, is not based upon facts. The assumptions used to reach those conclusions were in error. The “logistical problems” of delivering HBOT to the large numbers of war casualties are easy to solve. DoD medicine could repair a brain injured veteran with the full NBIRR protocol for about $480 worth of oxygen. That is just over the one-day cost of a service member not at his duty station ($375 enlisted, $425 officer). Once HBOT is adopted, military readiness would rapidly improve rapidly, without disrupting military training or service, and could even be used in theater during combat rotation, and during the stand down time after exposure to blast. The IHMA has provided these solutions and they have been submitted both to DoD medicine and the U.S. Congress. This would be far superior to the unofficial reports we have heard of ½ of the current combat force being “unable to cross the wire” because of accumulated blast injuries during multiple combat rotations.
Comparative Effectiveness Research, well characterized in the current Administration’s health care reform bill, customarily uses Bayesian statistical methodology to determine whether one therapy or another is better. As Dr. Harch has publically stated, the practice of medicine, by its nature, is Bayesian. This technique has always been used by surgeons to determine whether a new surgical technique is better.
Since hyperbaric medicine, proved efficacious in 1937, is already approved for 13 indications, 3 of which are non-healing wounds, and 3 of which are for neurological indications, the placebo effect has effectively been ruled out. As one former military physician stated yesterday in our conversation, “this sounds pretty on-label to me.”
Under Bayesian Analysis, pre-treatment and post-treatment objective measurements are used to determine whether one therapy is better than another therapy. If there is statistically significant improvement, the methodology can determine which technique is more effective.
The CDC, VA and CMS are all now using Bayesian Analysis in their various studies. Dr. Kuppersmith, head of VA research, told us that they were now using this methodology throughout the VA for their studies. Ann Albright, head of CDC’s Diabetes Division, told Dr. Harch, Dr. Wright and me that they are using Bayesian analysis now for most of their research. Based upon this methodology, the Centers for Medicare and Medicaid Services was able to start their “Coverage with Evidence” program. CMS contended for years that they could not use funds that the Labor HHS Appropriations committee gave them to conduct research because they could not, by law, pay for “no treatment” as was required under the RCT model.
Bayesian Analysis has liberated social science and health care policy from the randomized-controlled trial model. This includes RCTs excessive costs and flawed results. One reason the FDA has adopted this technique is that many RCTs have yielded incorrect conclusions because of poor study design. This has causes significant financial losses in the medical system that relies on accurate information, and caused harm to many thousands of patients. (VIOXX for example.)
The RCT model, Dr. Duncan, our Vice President for Development, contended when writing the Medical Information and Treatment Access Act (MITA), is inappropriate for study of the active medical off-label use for already approved drugs and devices. The legislation was crafted in 1996 with the late Dr. John Eisenberg the AHRQ Founder. The mechanisms of action and risks are known for these items. The RCT method ignores everything you already “know,” while the Bayesian Analysis system allows acknowledgement of what is known. In order to study medical practice, in situ, Bayesian Analysis is necessary.
With the approval of this FDA Bayesian guidance, we now have complete validation of that philosophy from the FDA Devices Division. RCTs are still valid for new synthetic molecules for which they were originally designed. The RCT system is also inappropriate for nutritional supplement research. It is unethical, for example, to withhold calcium from a person’s diet since the detrimental effects of that action are well known. We have the results of the nutritional experiments in the Nazi concentration camps, from which our own “Minimum Daily Requirements” document was first published in 1949. There have been many RCT nutritional studies that came to grossly flawed conclusions.
Biological mechanisms of action for oxygen, and oxygen saturation of tissues, are now well characterized. Many of these mechanisms are known all the way to DNA sequences activated. No one can claim HBOT has a significant placebo effect and be grounded in any kind of science. The only way one can come to that conclusion is through a poorly designed RCT study, such as the poorly designed Collette Study HBOT for Cerebral Palsy in Canada. This study was conducted after U.S. military had already validated HBOT 1.5 as being effective for CP, a white matter injury to the brain, in a published study.
It should be noted that the study design for Air Force HBOT Wound Care protocol study currently being conducted in Texas, and the as yet unapproved DoD HBOT for TBI study repeats the design flaw of the Collette study. The Army and Navy SGs have been informed that “the placebo” is actually a therapeutic dose of oxygen. They have chosen the FDA-approved protocol for mountain sickness, compressed air at HBAT 1.3, with 30% more oxygen delivered to the subject’s tissue. The U.S. Army Surgeon General, Navy Medicine, and the DoD and Civilian Primary Investigators, CAPT Brett Hart (USN), and Lin Weaver, M.D. former UHMS President, were provided with that information and have also been provided with the correct placebo technique by the IHMF should they insist on using a placebo group in their study. To our knowledge, to date they have insisted on using this flawed placebo. The Air Force wound care protocol is too high a dose of oxygen, and will likely not yield the kind of results that we have seen to date with the NBIRR-01 protocol. This protocol is based upon 20 years of clinical experience and well-characterized hyperbaric oxygen dosing first published by German neurosurgeons in the 1970s. Information we have indicates that the DARPA study by Dr. Cifu in Richmond will use a true placebo.
Check and see what the FDA-Devices Division has written about Bayesian Analysis.
“FDA Devices Division Bayesian Guidance-2010” 
“FDA Devices Division Draft Bayesian Guidance-2006”
