The Ethics of Off-label Use of HBOT

More than 20 years ago, when I was the president of the Undersea and Hyperbaric Medical Society (UHMS), there was a lot of interest in using hyperbaric oxygen therapy (HBOT) for cerebral palsy (CP). An organization comprised of the mothers of children with CP decided that, as UHMS President, I was personally responsible for preventing insurance companies from covering HBOT for their children. Ironically, at the time (1998), I was consumed with the fight to get Medicare to cover HBOT for diabetic foot ulcers (DFUs). A group of us flew to Washington, D.C. every few months for another meeting with officials from the Centers for Medicare and Medicaid Services (CMS). The decision of CMS to cover HBOT for Wagner Grade 3 DFUs was a hard-fought battle by many people, which took 2 years. Given how hard it was to get Medicare coverage for DFUs when there were randomized, prospective clinical trial (RCT) data to support its efficacy, it was ironic that an advocacy group thought I could influence insurance coverage policy for an experimental indication.

One afternoon, I was sitting rather despondently in the Doctor’s dining room when a young woman asked to share my table. By way of making conversation, she said she saw in the university newspaper that I’d recently become president of something. She asked this very insightful question, “What do you think your biggest challenge will be?” I told her I thought it would be the ethics of providing HBOT for unproven indications, and she said, “That’s interesting because I am an ethicist.”

Thanks to that chance meeting, Dr. Evelyn Chan and her mentor, the well-known bioethicist, Dr. Baruch Brody, agreed to do a formal review of the ethics of hyperbaric oxygen therapy in “off-label” conditions, published in 2001 in Undersea and Hyperbaric Medicine.(1) That ethical review has stood the test of time, and I will summarize a lot of it here.

What does it mean for an indication to be “Off-label”?

Hyperbaric oxygen chambers are medical devices that are cleared for marketing and use by the Food and Drug Administration (FDA) for 13 indications, based on a list originally compiled by the Undersea and Hyperbaric Medical Society (UHMS) (2,3). These 13 indications are considered “on-label” use of HBOT by the FDA, and the use of HBOT for any other indications is considered “off-label” by the FDA.(4) The UHMS added idiopathic sudden sensorineural hearing loss (ISSHL) to its list of approved indications (1), but the FDA does not recognize this indication, which means that the treatment of ISSHL is considered “off-label,” even though it is on the UHMS approved list.

Ethical Principles

The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles for medical research involving human subjects. The Declaration includes the following statement:

“In the treatment of an individual patient, where proven interventions do not exist or other known interventions have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legally authorized representative, may use an unproven intervention if in the physician’s judgement it offers hope of saving life, re-establishing health or alleviating suffering…“(5)

This means that the use of HBOT, regardless of whether it is used on-label, off-label, or as part of a research protocol, is ethical only when the potential benefits outweigh the risks to the patient. The decision to use HBOT for any indication involves a “risk benefit” assessment.

The Practice of Medicine vs. Research

Many drugs and devices are used almost exclusively for off-label indications

because over time, real-world experience demonstrated that their best use was not for the indication that had been evaluated by the FDA. In the practice of medicine, physicians can make “case by case” decisions to use HBOT for an off-label indication. The fact that a specific indication for HBOT is off-label does not mean that an IRB (Institutional Review Board) approved research protocol must be in place to treat a patient.

However, if patients are being treated on a “case by case” basis for an off-label indication, then data cannot be collected in a prospective way. Once you start collecting data, then an IRB must be in place.  In other words, when HBOT is performed with the intent to gather and apply information to the care of other patients, the clinician is engaged in “research” and an IRB approved research protocol is required. Patients must also sign a consent to participate in research. The IRB process must be followed even to enroll patients in an anonymous patient registry.

Off-label or “Compassionate” use of HBOT

Obtaining informed consent is a necessary part of providing HBOT (or any medical treatment) regardless of whether the use is “on-label” or “off-label.” However, the process of informed consent takes on even greater importance when it involves the off-label use of a medical device like HBOT. Although informed consent does not have to be written, since the physician needs to document the details of the consent process, it makes sense for this to take the form of a written document.

For the patient to make an informed decision regarding the off-label use of HBOT, the physician must disclose the usual risks of HBOT (e.g. otic barotrauma, oxygen toxicity, etc.) as well as the following information(4):

• HBOT is not proven to be of benefit in the treatment of the condition
• Whether there are alternative medical treatments for the condition
• The level and type of scientific data that support the use of HBOT
• The risks of HBOT that are specific to the patient, given their level of illness
• Exactly how much the treatment will cost the patient (since insurance cannot be billed for off-label use of HBOT)

Take Away Message
Many people have asked if it is ethical to use HBOT to treat a patient with COVID-pneumonia. The answer is that HBOT can be provided for any off-label use on a case-by-case basis without an IRB-approved protocol, if the potential benefits to the patient outweigh the risks of treatment insofar as can be determined, if the patient is informed of all the risks, if the patient is informed of available alternative treatments, and if the cost of therapy is clearly understood by the patient.

However, if data are being collected with the intention of using that information to direct the care of future patients, then the activity should be considered human research and IRB approval is needed, even if the research consists of entering data into a de-identified prospective registry.

For some hospitals, medical practices and organizations, the barriers to obtaining IRB approval of a research protocol can be significant. In addition to the absence of funding for trials involving HBOT, some hospitals do not have a defined IRB process, the institution may not carry the necessary liability insurance for human research, and there may be no physicians trained to perform human research. While we always prefer to have patients enrolled in an IRB approved trial (so that we can understand its potential benefit) is important for practitioners to know that they can ethically administer HBOT on a case-by-case basis for “off-label” indications.

Caroline E. Fife, MD, FUHM
Medical Director CHI SLEH Wound Clinic
The Woodlands, TX
CMO Intellicure, Inc.

References

1. Chan EC, Brody B. Ethical dilemmas in hyperbaric medicine. Undersea Hyperb Med. 2001;28:123–30.
2. Undersea & Hyperbaric Medical Society (UHMS). Indications for Hyperbaric Oxygen Therapy. UHMS, 2015. HBO Indications – Undersea & Hyperbaric Medical Society (uhms.org). Accessed 15 April, 2021.
3. Food and Drug Administration. Regulatory Information. FD&C Act Chapter V: Drugs and Devices. Updated September 25, 2015. FD&C Act Chapter V: Drugs and Devices | FDA (Accessed 15 April, 2021.
4. Fife CE, Eckert KA, Workman WT. Ethical issues, Standards, and Quality Control in Practice of Hyperbaric Medicine. In: Textbook of Hyperbaric Medicine. 6th ed. Ed: Jain KK. Springer, New York, 597-608, 2016.
5. WMA DECLARATION OF HELSINKI – ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS (https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/)