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Hyperbaric Medicine Officially Enters the Prohibition Era

Physicians' Forum Counterpoint
from Volume 1 Issue 1
Research in Hyperbaric Medicine

By Paul G. Harch, M.D.

The Physicians' Forum article in the inaugural issue is a comprehensive discourse with many good points on the legality of off-label HBOT, research funding, a registry, recommendations for patients seeking off-label treatment, and standardized testing/documentation. However, these points are nearly lost in an extremely confusing, obfuscating tangle of terms, definitions, and concepts that is partly based on a double standard. Despite the confusion, the message and threat to the entire hyperbaric medicine community was transmitted so loud and clear in the final paragraph that I was moved to declare this the "Prohibition Era Of Hyperbaric Medicine." It appears that the purpose of the article is to alter the historical method of the practice of medicine and hyperbaric medicine by jeopardizing a physician's membership in a medical society should they dare to use HBOT for an off-label indication.

The article begins with a comment on "evidence-based medicine" and then proceeds to speak about peer-reviewed, randomized, prospective, controlled, double-blinded trials (RCPT's) to assess validity of scientific information. The double standard in these two paragraphs can be appreciated in the 1996 approval of intracerebral abscess (ICA), (cerebral abscess, subdural empyema, and epidural empyema) by the Hyperbaric Oxygen Therapy Committee to the accepted indications list. The argument in the 1996 HBOT Committee Report was based on thirteen cases treated off-label, ten of which were published in the Journal of Hyperbaric Medicine, 1989. These were combined with six cases generated after years of open solicitation from an influential HBOT Committee member to any UHMS physician who had treated cerebral abscess with hyperbaric oxygen. These last six cases are strongly biased since very few physicians are willing to volunteer a personal/ professional failure, i.e., a hyperbaric oxygen treated cerebral abscess case that died. The mortality from these twenty cases was compared to the latest figures, 1991, on the historical declining mortality rate in cerebral abscess to achieve statistical significance and approve cerebral abscess as an accepted indication. To summarize, the accepted indication, cerebral abscess, is a diagnosis composed of three separate diseases, based on twenty non controlled cases, none of which appear to be on an IRB-approved protocol, all of which were apparently treated off-label, only ten of which are in a peer reviewed journal, six of which are highly biased, non-published solicitations, and the argument for which is based on a comparison to a historical declining mortality rate. Regardless of the strong pathophysiological argument, this is weak science, especially when compared to data discussed below. To subsequently argue, in the Physicians' Forum article's lead paragraph for evidence-based medicine from randomized, prospective controlled research published in peer-reviewed journals as an intro and backdrop to a critique of HBOT/ cerebral palsy and off-label use of HBOT, is a double-standard.

The double standard is more apparent in the article's review of HBOT/cerebral palsy data. The article disparages the HBO treatment data of cerebral palsy children by labeling it "anecdotal." This "anecdotal" experience includes six reports: 240 "anecdotal" cases by Machado, a single "anecdotal" case reported by me in 1994 (the first cerebral palsy case treated with HBOT in North America), three "anecdotal" cases reported by Dr. Neubauer and me at a hyperbaric meeting in Buenos Aires in 1996, an additional "anecdotal" case reported by Neubauer and me in the Third Edition of K. K. Jain's Textbook of Hyperbaric Medicine in 7/99, 18 "anecdotal" predominantly IRB cases reported by me at the Boca Raton July 1999 Conference, and now 25 IRB "anecdotal" cases reported by Montgomery at McGill in 1999. While a number of the above reports are abstracts, three of the studies (Machado, Harch, and Montgomery) are prospective and controlled (each patient serving as his own control). The Montgomery study also used blinded examiners and was published in a peer-reviewed journal. This constitutes greater experience for HBOT treatment of cerebral palsy than for the nineteen "anecdotal" HBOT/ICA cases which generated inclusion on the accepted indications list in 1996. To disparage the evidence for HBOT/CP is inconsistent.

A final illustration of this double standard, the possible importance of a proponent for' the new indication and the complexity of the approval process, is provided by the case of HBOT in acute traumatic brain injury (TBI). There have been three RCPT's with positive results (Holbach 1975, Artru 1976, Rockswold 1992), a number of companion articles on the same, and a plethora of articles showing beneficial effects of HBOT on the underlying pathophysiology of acute TBI, including eight articles on HBOT reduction in cerebral edema used to argue for cerebral abscess in the 1996 HBOT Committee Report. The last trial on HBOT/TBI was the impeccable Rockswold study in 1992, a six year RCPT with blinded evaluation of 168 acute, severely brain traumatized individuals who underwent two weeks or less of HBOT, beginning nearly twenty-six hours after their head injury. The endpoints were completion of the two-week HBOT protocol, wake up, or death during the two weeks. The results were an HBO induced 47 percent reduction in overall mortality rate and a nearly 60 percent reduction in the most severely traumatized group. This is the greatest reduction in mortality rate (the same outcome as brain abscess) in acute TBI in the history of medicine using an unassailable study design, and yet it is not on the approved indication's list. Why not? This is inexplicable. Possibly, there is no champion for this indication. Unfortunately, the discussion of evidence-based medicine, RCPT's, and peer reviewed journals in the Physicians' Forum article is meaningless in the face of the cerebral abscess/acute TBI inconsistency; this is just one of several that space limitations preclude discussing here. Furthermore, it misleads the reader into assuming that an RCPT is the sole standard for inclusion on the accepted indication's list. Unequivocally, it is not. The HBOT Committee's recent decision to review existing indications and assess new indications based on rigorous scoring systems devised by Dr. Sheldon Gottlieb and the American Heart Association may rectify some of these inequities.

Following this introduction the article becomes extremely confusing and immerses the reader in dizzying complexities and politics as it discusses investigational drug exemptions (IND's) and investigational device exemptions (IDE's). Curiously, after 40 years of clinical hyperbaric medicine the FDA has only had one application for a hyperbaric IDE. Essentially, in the history of hyperbaric medicine in the United States every human study, except one, has been published without an IDE or IND. What has all of a sudden changed the FDA's mind? In the answer to this question lie some of the underlying problems in the hyperbaric medicine community today. It has been claimed by some that the FDA made the first move by approaching a medical society because of their concern over HBOT for off-label indications/chamber safety. If so, why was this an unannounced, closed door meeting with a restricted attendance? The situation is actually more complicated. If in fact the FDA is concerned about off-label HBOT use by physicians and non physicians and chamber placement in private homes, what do any of these subjects have to do with HBOT research, IDE's, and IND's? The answer is, nothing! Off-label practitioners and home users are almost uniformly not performing research. Only a very few have documented their cases, even less have presented them at conferences, and most of the documentation was initially intended to prove efficacy to obtain insurance or other third party reimbursement. The article is obfuscating and seems to suggest that the FDA intends to intervene in the practice of medicine, an intention that both the FDA and the article openly deny. What it also suggests is that any physician who wishes to do hyperbaric research needs to apply for an IND or IDE from the FDA. This is directly contradictory to recommendations from the FDA in 1992 and 1993 on designing a hyperbaric clinical trial. The sole criterion for FDA involvement, IDE's, and IND's was whether or not the treatment or device posed a significant medical risk. With a previously approved medical device that routinely treats with impunity elderly, ill diabetics as well as children and has a long insignificant risk safety profile, e.g., a hyperbaric chamber, one only needs their local hospital IRB, not the FDA. To suddenly change this policy and rewrite the rules that governed 40 years of clinical hyperbaric medicine research, one has to declare HBOT a significant risk medical treatment and device. This flies in the face of the millions of safely performed HBOT's worldwide. One would also have to explain the results of the recent HBOMEDTODAY on-line poll of hyperbaric units which showed that the majority of the more than 400 facilities in the poll have INTERMITtENT OR NO PHYSICIAN ATrENDANCE during HBOT's. Does the FDA consider HBOT a significant risk in light of this data?

Again, I ask the questions: why has the FDA supposedly changed their policy or have they? Has anyone seen a written confirmation by the FDA of the article's assertion, and who brought the FDA into this confusing arena after 40 problem free years? In the answers to these questions is found an explanation of the attack on off-label use of HBOT/free-standing HBOT centers and possibly my confusion after reading this article. In my opinion, one of the obvious answers is money. HCFA just reduced hyperbaric medicine Part A reimbursement to $210, disbelieving the $350/treatment cost proposed by the Lewin Group. When added to Part B (Professional) reimbursement of $130, the total becomes $350, vs. $500 before the HCFA reduction. What will happen to hospital-based reimbursement when HCFA realizes that free-standing physician-attended facilities are charging $150-200 for the combined fee? It might drop again. There are powerful forces opposed to this.

The article then compounds the above confusion with a discussion of the terms "investigational, experimental, and unproven" and in the process confuses the terms with off-label use of an approved medical device or drug and the clinical practice of medicine. An illustration of this is best appreciated by referring to the UHMS accepted indications list and the 1999 Medicare/Medicaid list. The article considers only the 13 indications on the UHMS list as proven (see cerebral abscess above); everything else is experimental and unproven (see acute traumatic brain injury above). As pointed out in the 1999 7th Annual

Advanced Topics Course in Columbia, South. Carolina in the lecture on Hyperbaric Oxygen Therapy in Chronic Neurology, Medicare and Medicaid only recognized eight of the UHMS indications, but reimbursed for at least five additional "off-label" non-(UHMS/ FDA) indications. In essence, every time a physician in the United States treated for one of the five or more non-UHMS Medicare/ Medicaid indications, they technically treated off-label, were reimbursed for, and profited from an "unproven, experimental" treatment. The conundrum is that the article's restrictive definition of "proven/non experimental" forced the federal government to reimburse for "unproven experimental" indications, a situation which is illlegal according to HCFA/Medicare. A second problem with this definition is that non-hyperbaric physicians routinely ask their patients to sign consent forms for off-label use of FDA approved medical devices and drugs without declaring them experimental. Why should hyperbaric physicians be any different? If you treated someone for acute TBI, do we say that, it is experimental and investigative simply because it's not on the UHMS list when in fact the data in support of it is far greater than cerebral abscess or certain other UHMS indications that are poorly supported by less scientific data? This makes no sense. It makes even less sense when the argument extends internationally. The Russians routinely treat for perinatal fetal ischemic/hypoxic conditions, stroke, and neurological diseases, the Chinese for pediatric and adult neurological indications, the Japanese for certain cerebral conditions, and the northem French for near-hanging. All have published data to support their

practices. In particular Dr. Mathieu had 350 consecutive cases of near-hanging by June 1998 to add to his historically controlled trial to underpin HBOT for near-hanging as the standard of care. Because they are UHMS members, should they cease treating these diagnoses because it is "unproven and experimental" by someone's definition? Of course not. Again, this is nonsensical.

Unfortunately, the article's discussion then devolves into the distorted concept of "profit." As it tums out, "research" appears to be no more than one doctor's disapproval of another doctor's practice while "profit" means that same doctor's disapproval of the other doctor's fees. If we evaluate what is claimed as "profiting" from the use of hyperbaric medicine in off-label fashion, the market has supported hyperbaric use for off-label indications at $50-200/ treatment ($150-200 for physician attended free-standing facilities, much greater charges at hospital-based centers). If there is such bounty in off-label HBOT why is the hyperbaric medicine community not rife with everyone "profiting" from off-label treatment? The answer is that at $50-200/treatment there is very little, if any, profit. Compare this to the commonplace $1,000/treatment total charge of hospital-based hyperbaric medicine. "Profit" is an abused word.

The article makes excellent recommendations to people seeking off-label treatment, commenting on physician attendance, training requirements, chamber certification, etc. These are well argued since HBOT is a medical treatment, medical treatments are usually delivered in the United States by physicians, drugs are dosed by physicians, and HBOT is a drug. Unfortunately, the article confuses these issues by mixing them with concepts that include investigational device exemption, off-label use, and experimental treatment. You don't need an investigational device exemption to treat for an off-label disease and to treat for an off-label disease the discussion omits the key reason that people seek and increasing numbers of facilities provide off-label treatment or treatment for any medical therapy: to see if the treatment can improve the patient as it has improved others with the same or a similar condition. That treatment may also contribute to medical knowledge as it has throughout the history of hyperbaric medicine where such information has formed the basis for many of the accepted indications. [One needs to look no further than all of the international congresses and symposia, the UHMS meetings/workshops, and in the UHMS journals where multiple cases are reported on HBOT in various conditions; almost none of them involved IDE's, IND's, IRB's, or experimental protocols (see cerebral

abscess above)]. Furthermore, for off-label treatment no institutional review board needs to approve a protocol and no one needs to put "experimental" on a consent form any more than you need to make a patient sign an experimental consent form for the five or more "unproven" Medicare/Medicaid HBOT indications, use of Neurontin for an off-label indication, meaning anything except seizures, the use of anti-depressants for anything but depression, chiropractic therapy, chelation therapy, or a variety of other medical treatments available in the United States.

The final paragraph in the article is the most disturbing, yet the most revealing, and is the reason I have dubbed this inaugural period of the new millennium THE PROHIBITION ERA OF HYPERBARIC MEDICINE. In a single sentence, the article's confusion clears and the bottom line emerges. After the above discussion of double-standards and arbitrariness of inclusion/exclusion of certain indications on/from the accepted indications list, it is exceedingly unclear "what the rules are" that the article refers to and what "the UHMS expects its members . · . to abide by" The message, however, is loud and clear: IF YOU TREAT FOR OFF-LABEL INDICATIONS, BEWARE OF REPERCUSSIONS FROM THE UHMS OR FDA. This directly contradicts the article's statement that off-label treatment is legal and that the FDA doesn't interfere in the practice of medicine.

It is more important to realize, however, that neither the UHMS, nor any individual has any business interfering in any physician's practice, even if the physician's a member of the UHMS. It is this interference that is responsible for the PROHIBITION ERA OF HYPERBARIC MEDICINE in the United States. We now have physicians anonymously admitting to off-label treatment (see Feb/ April issue of the MUMS Newsletter Editorial read before the closing session of the 7th Advanced Topics Course, 4/99, Columbia, South Carolina) out of fear of reprisal, hyperbaric technicians mounting chambers on trucks and traveling around the country to deliver HBOT, and private moms and dads putting hyperbaric chambers in their homes. This directly leads to the article, "Hyperbaric Chambers in Homes; What Went Wrong?", that follows the Physicians' Forum article. Simply, some poor individual was trying to treat himself for a post concussion syndrome because he couldn't obtain the same by a local physician, presumably because there's no proof (see the Barrett, Harch, Mader HBOT/chronic TBI study presented at the 1998 UHMS and American Academy of Neurology meetings). We are not far from Speakeasy hyperbaric centers and black market hyperbaric medicine as a few individuals are forcing underground any HBOT outside the accepted indications.

Looking beyond this article and speaking generically, the sad reality of this spectacle is that in the recent history of hyperbaric medicine we have had a small group of individuals who can't play in the same sandbox with everyone else. Through the: veil of institutional protection they've pursued their distaste of others with words, jumping from one self-defined term to another, leaving us with a convoluted set of guidelines that confuses the clinical practice of hyperbaric medicine. Not content to just be intolerant, some of these doctors have aggressively attacked those who practice outside their rigidly confined perceptions of the practice of medicine. The most notable example has been the private and public disparagement and character and professional assassination of Dr. Richard Neubauer in South Florida, over the past twenty years. There are now three well-placed members of the UHMS with whom I have spoken, two physicians and one Ph.D., who, starting with Dr. Gottlieb (Ph.D.) when he was chairman of the Education Committee of the UHMS, heard such damaging slanderous statements about Dr. Neubauer that they made personal journeys to his facility to responsibly investigate the criticisms before joining the chorus of damnation. Dr. Gottlieb became Dr. Neubaner's partner and the other two are vigorously supporting colleagues. All of them, however, were shocked at the unfounded criticisms of Dr. Neubauer and

the Grand Canyon of disparity between the accusations and reality. What has Dr. Neubauer done to deserve this? He has published and presented data at countless meetings, yet because he has charged a nominal fee for his services, $200/treatment (vs. $1,000-1,100 in hospital-based practices) he has been ridiculed by these other doctors and publicly and privately trashed throughout the United States hyperbaric medicine community. In contrast HE IS CELEBRATED AND WELCOMED INTERNATIONALLY: he is responsible for the introduction of HBOT to the World Federation of Neurology, was the impetus for the current HOTFAST Trial (Hyperbaric Oxygen Therapy for Acute Stroke) that commences in July 2000 at a dozen centers in the United States, will be conducting his second consecutive invited workshop by the European Federation of Neurological Societies, and saved the U.S. HBOT community, not once, but twice when HCFA threatened the survival of HBOT. In the meantime, he and others have been repetitively pursued because they dared to treat outside various recommendations of certain members of the UHMS. Supposedly, the UHMS has now passed a by-law that confers authority to punish its members. Curiously, the vote has never been announced and there are numerous physicians who never received ballots. A pall has been cast over the hyperbaric medicine community by this continued overt and covert threat about, as the article says, the UHMS expecting its members to abide by FDA and other rules. This is in a complete contradistinction to the practice of medicine and the history of the UHMS where so much of the data that has been generated to date has been accumulated from non-controlled, non-IRB, off-label use of HBOT. We now have a hyperbaric medicine community where members of the UHMS are fearful of treatment of any off-label indication lest they be reported to the hierarchy of the UHMS, the HBOT police, and now the FDA? As if physicians don't have enough to worry about.

At a time when economic extinction by HCFA has threatened hyperbaric medicine, no physician needs an additional professional threat. We should continue to do good research, separate research from the clinical practice of medicine, and prove efficacy of treatment to the satisfaction of the medical and lay public. Most important, we need to allow doctors the freedom to practice medicine and in the process generate the serendipitous findings that make their way to academic institutions where they become "great discoveries." This freedom is the essence of the practice and art of medicine and that inviolate physician right with which no one should interfere. After all, if the FDA doesn't interfere, why should anyone else?
Paul G. Harch, M.D.