Article by Dick Clark on National Baromedical Services

On May 15, I submitted an Emergency Use Authorization request, seeking FDA approval for hyperbaric oxygen (HBO) treatment of COVID-19 disease. You can read the entire submission in a link provided at the end of this blog. The ability of HBO to overcome limitations with normobaric supplemental oxygen in the setting of worsening hypoxia is indisputable, and several authors had already described its compassionate use. While these studies were retrospective and involved small numbers of patients, reported outcomes and related safety data are encouraging enough to warrant further attention. In fact, a number of controlled clinical trials are in various stages of development to do just that. My position was that if the FDA approved the EUA, hyperbaric medicine would no longer be off-label for COVID-19 patients and increasing numbers of hospitals may be more inclined to offer humanitarian HBO access. This was certainly the case at our facility here in Columbia, S.C., where the critical care team was not prepared to venture into its off-label use.

Resulting Conference call

The FDA acknowledged my application and scheduled a conference call on June 1. Leading the FDA on the call was the Assistant Director, Division of ENT, Sleep Disordered Breathing, Respiratory and Anesthesia Devices. While cautiously optimistic that the FDA would be favorably disposed, I was left disappointed. They denied it for reasons not entirely convincing. One example was that I was unable to provide evidence of HBO’s effectiveness for this disease, which I felt a rather odd position to adopt, as COVID-19 was new. I had argued HBO’s convincing biologic plausibility, that of its ability to readily overcome tissue hypoxia.

Given my understanding that the FDA had recently approved a EUA for extra corporal membrane oxygenation for COVID-19-related hypoxia, and knowing that HBO was a far superior oxygen delivery technology, I asked what COVID-19 effectiveness data had accompanied the ECMO request. They pointed out that they had granted ECMO “Immediately-in-Effect” approval, rather than a EUA. I have since been unable to determine the precise distinction between the two, as they appear quite similar. No effectiveness data had appeared to accompany the ECMO request. As I noted in my EUA application, early ECMO COVID-19 data is disappointing to say the least.

The FDA pointed out that providers were free to order HBO off-label, so no need to consider the EUA. I replied that this would presumably be the case for ECMO. The FDA did not reconcile this. They then argued that it would take months to build a multiplace chamber and knock down hospital walls to get it installed/operational. I responded that if chambers were not already available at interested hospitals, a monoplace chamber, the type used in two of the three above referenced reports, could likely be delivered and functional within a matter of weeks. The FDA referenced the Undersea and Hyperbaric Medical Society position that HBO use should only occur within a formal clinical trial. My reply as that while aware of this position, awarding a EUA would offer current COVID-19 patients access during the considerable period required for such trials to be generated, conducted, analyzed and reported. It would also offer a pathway for hospitals unwilling/unable to develop trials de novo, or collaborate with existing trials, due to resource limitations, particularly given the financial effect of COVID-19 on hospital budgets. Finally, the FDA expressed concern that data on patients not enrolled in formal trials would be unavailable for analysis of effectiveness. My reply was that of the three centers involved HBO’s compassionate use, two have already published their results and third anticipated to do so.

Which brings me to the title of this blog.

FDA Concern regarding Lack of Efficacy Data

When pressed on my inability to provide effectiveness data to support HBO for COVID-19 disease, I pointed out that when the FDA first approved their current 13 uses of the hyperbaric chamber, none had undergone efficacy analysis and few enjoyed compelling effectiveness data. Their response was somewhat brutal. They said that the FDA’s role in approving HBO “was unique”, in that “those uses were grandfathered in without strong supporting evidence”, suggesting HBO would not pass muster in the modern era where the need to prove an intervention works as advertised is imperative. They added, “No new FDA indications would be allowed without corroborating efficacy data”.

To give the FDA its due, they have a point. There really is a dearth of high quality evidence to substantiate the role of HBO therapy in modern medical practice. While it is improbable that anyone would argue the need for better data to support decompression sickness as an indication, divided medical opinion continues to exist for many of the more common uses.

Efficacy vs Effectiveness

A quick reminder of important distinctions between efficacy and effectiveness data:

Efficacy studies usually precede effectiveness studies. They address the question; does a therapeutic intervention work under ideal circumstances? This invariably involves sham controlled, strictly enforced, and usually blinded clinical trials, with highly selected patient populations and numerous exclusion criteria.

Effectiveness studies seek to determine if data produced from efficacy research is translatable to real-world practice, namely the everyday clinical setting. It opens up to analysis of heterogeneous populations with some flexibility, few exclusion criteria, and takes into account concurrent interventions, adherence to dosing protocols and patient compliance.

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