Re: Patel et al.: Considerations when offering minimally proven investigational treatments (Ophthalmology. 2023;130:351–353)
Authors: Robert K. Maloney
Journal: Ophthalmology (2023)

Patel et al1Patel S. Kim S. Sternberg Jr., P. Considerations when offering minimally proven investigational treatments.Ophthalmology. 2023; 130: 351-353Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar in their otherwise excellent editorial, make one significant error: they confuse "minimally proven" with "investigational." This confusion is evident even in the title. It is important that health care providers understand the difference between minimally proven treatments and investigational treatments. The founding document that defines the ethics of human subject research in the United States is the Belmont Report.2The Belmont Report.www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.htmlDate accessed: May 15, 2023Google Scholar The Belmont Report defines "practice" as interventions designed solely to enhance the well-being of an individual patient with a reasonable expectation of success. In contrast, "research" indicates an activity designed to test a hypothesis or permit conclusions to be drawn, thereby, developing or contributing to generalizable knowledge. The authors note that up to 73% of outpatient medications prescribed for off-label use have little or no scientific support. The medications are being used in routine practice in ways that are minimally proven, but the medications are generally not being used in an investigational manner. The prescribing physician expects the treatment to be successful and his or her purpose in treating is solely to enhance the well-being of the patient. Most of us have encountered a situation in the operating room for which there may have been little precedent in the medical literature. We have relied on a lifetime of experience to complete the case. We certainly performed unproven treatments in these cases, but these treatments were not investigational because their sole purpose was to benefit the patient. Confusion is common in this area because there is considerable overlap between "investigational" treatments and "minimally proven" treatments. Investigational treatments are usually minimally proven but need not be. A postmarket study of a United States Food and Drug Administration–approved treatment is investigational, but not minimally proven. It is not unusual for minimally proven treatments to be approached in an investigational manner, as the authors cite with the initial use of bevacizumab during the period before the approval of ranibizumab. Bevacizumab was used under institutional review board review, presumably because the authors' intention was to enroll multiple patients to determine in a systematic way whether the drug could treat neovascular age-related macular degeneration. However, a reasonable and ethical physician at that time might have performed an intravitreal injection of bevacizumab in a patient with impending visual loss in a monocular eye, given the strong data for the effectiveness of ranibizumab, with proper consent, as long as the purpose was solely to improve the well-being of the patient. Such a hypothetical treatment would not have been investigational. Practitioners need to understand the distinction between minimally proven and investigational treatment so they neither deny a needy patient an unproven treatment with a reasonable expectation of success or gather generalizable knowledge as part of routine practice without institutional review board approval. Considerations When Offering Minimally Proven Investigational TreatmentsOphthalmologyVol. 130Issue 4PreviewMany commonly performed medical interventions have never been evaluated rigorously to ensure that their risks do not exceed their benefits. As many as 73% of outpatient medications prescribed for an off-label use have little or no scientific support.1 The reasons behind this disconnect are myriad, including regulatory barriers, lack of adequately powered clinical trials, and absence of agreed-upon standards of care. With drug approval times taking an average of 8 years from clinical trial startup to full United States Food and Drug Administration (FDA) approval,2 investigational treatments may be the only option for patients with severe, life-shortening conditions. Full-Text PDF ReplyOphthalmologyVol. 131Issue 2PreviewWe appreciate the thoughtful critique of our editorial by Dr. Maloney and wish to take this opportunity to address the important distinction between "minimally proven" and "investigational" treatments. Dr. Maloney provides insight into the nuances essential for health care providers to grasp when navigating the complex landscape of medical interventions. Full-Text PDF