What is “Off-label” Use of HBOT?
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) (1, 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. 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.
COVID-19 pneumonia would be an “off-label” use of hyperbaric oxygen therapy. Do you have to have an Institutional Review Board (IRB) approved research protocol to treat a patient with HBOT for COVID-19 pneumonia? When DO you need to have a research protocol approved by an IRB?
What is the Practice of Medicine?
The fact that a specific indication for HBOT is off-label does not mean an IRB (Institutional Review Board) approved research protocol must be in place to treat a patient. Physicians can make case by case decisions to use a device or drug for an off-label indication. This is part of the practice of medicine. However, if patients are being treated on a “case by case” basis, then data cannot be collected in a prospective way and this includes entering data into an anonymous registry. If COVID-19 patients are being treated on a case-by-case basis, then no additional activities can occur beyond what is usual for a patient’s medical care.
What is Research?
When HBOT is performed with the intent to apply potential findings to the care of other patients, the clinician is engaged in “research.” This includes the collection of data into a registry. If data are collected (on paper or electronically), an IRB approved research protocol is required. Patients must sign a consent that is also approved by the IRB. The consent must clearly state that patients are subjects in a research study, and that they have the right to consent or decline to participate in the study. Furthermore, if they decide NOT to participate, their care will not be negatively affected. The IRB process must be followed even to enroll patients in an anonymous patient registry. Each participating institution will have to provide IRB approval (many institutions use a “central” IRB).
The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles for medical research involving human subjects. These principles emphasize the protection of the rights of human subjects, which includes their right to consent or refuse to participate in research after being fully informed of the risks and potential benefits. 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)
The use of HBOT, whether on-label or off-label, or as part of a research protocol, is ethical only when the potential benefits are greater than the risks to the patient. As information about HBOT in COVID-19 pneumonia becomes available, it may demonstrate that the nominal risks of HBOT, even for relatively sick patients, are less than the risk of intubation with COVID-19 pneumonia.
Informed Consent for Off-label or “Compassionate” use of HBOT
Off-label or “Compassionate” use of HBOT is not unethical assuming certain standards are followed as part of the informed consent process. Off-label use of drugs and devices is commonplace in the USA.(4) Obtaining informed consent is a necessary part of HBOT 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 COVID-19 pneumonia
- The existence of alternative medical treatments for the condition
- The level and type of scientific data that support the use of HBOT for COVID-19 pneumonia (e.g. anecdotal but consistently encouraging results).
- The risks of HBOT that are specific to the patient given their level of illness
- Exactly how much the treatment will cost the patient (Insurance cannot be billed for off-label use of HBOT, although how treatments for COVID-19 pneumonia will be handled by payers is not known.)
COVID-pneumonia is an off-label use of HBOT. It can be provided 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 alternative treatments, and if the cost of therapy is clearly understood by the patient.
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 investigating HBOT and COVID-19 pneumonia, 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. When an IRB-approved protocol is not available in a timely way, it is important for practitioners to know that they can ethically administer HBOT on a case-by-case basis. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act in the patient’s best interest when providing medical care.”(5)
- Undersea & Hyperbaric Medical Society (UHMS). Indications for Hyperbaric Oxygen Therapy. UHMS, 2015. https://www.uhms.org/resources/hbo-indications.html. Accessed 23 July 2015.
- Fife WP, Fife CE. Textbook of hyperbaric medicine. In: Jain KK, editor. Hyperbaric oxygen therapy in chronic Lyme disease. 5th ed. Germany: Hogrefe & Huber; 2009. p. 149–155.
- S. Food and Drug Administration. Regulatory Information. FD&C Act Chapter V: Drugs and Devices. Updated September 25, 2015. http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/FDCActChapterVDrugsandDevices/default.htm. Accessed 30 September 2015.
- Chan EC, Brody B. Ethical dilemmas in hyperbaric medicine. Undersea Hyperb Med. 2001;28:123–30.
- 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/).