In reaction to the speed and severity of the COVID-19 pandemic, the medical community has responded by sharing, collaborating, and advancing therapies from basic science to the bedside at a faster pace than ever before. From an ethics perspective, deploying treatments and sharing experience before meeting standards for evidence-based practice has both potential risks and benefits. These risks and benefits must be carefully balanced.
During times of crisis, innovations are necessary to develop and guide effective treatment strategies. We generally hear about these novel approaches early, as a result of small studies, case reports, or non-peer reviewed information dissemination. Most of these innovations have not been through the rigor of adequately powered trials, certainly not the gold standard of double-blind randomized controlled studies. Waiting for the gold standard limits our ability to provide the best possible medical care, as understood at the time. Sharing and implementing real time innovations can be appropriate and helpful both to bridge the gap until better evidence is available and to accelerate knowledge dissemination and the idea/hypothesis generating process.
While expert opinion is one of the lower forms of evidence, it is superior to uninformed practice. In many instances, unless and until we are convinced of the possibility of harm from these treatments, it is appropriate to implement them. For new therapies colloquially called “compassionate use,” the preferred terms are either “off-label” (drug or device that is Food and Drug Administration [FDA]-approved for one use but being considered for another) or “expanded access” (a drug or device that is not yet FDA-approved). In traditional expanded access, both the patient and the physician request a treatment, the manufacturer agrees, and consent is obtained.
Early sharing of information can reduce information and experience asymmetry between areas impacted sooner or more heavily by a global health emergency and those that are impacted later or more lightly. It can also promote rapid crowdsourcing, innovation, and insights about therapies to be confirmed or rejected on a timeline that keeps pace with an ever-evolving threat.
Risks of Harm
When faced with the option of an unproven intervention, there is a cognitive bias towards intervention. Crises such as COVID-19 may exacerbate cognitive biases and misinterpretation of data and studies.1 The historical medical maxim to “first, do no harm” reminds us that we do have the ability to cause harm and that we must judiciously balance the intertwined principles of beneficence and nonmaleficence—pairing good intentions with an objective assessment that benefits are likely to exceed harms.
Some innovative treatments have been found to be harmful, as a recent trial using high-dose chloroquine (and azithromycin) in elderly COVID-19 patients suggested.2 Extrapolating from in vitro or uncontrolled, open-label case series can be dangerous. Ubiquitous harms from medications are the reason the FDA requires multiple phases of testing and ultimately, large double-blind randomized controlled trials before approval. Despite FDA rigor, multiple medications are retrospectively removed from the Prescriber’s Digital Reference and formularies each year due to postmarketing data demonstrating possible harms.
The application of sound science is a core tenant of medicine as a profession. Public confidence in the scientific grounding of medicine and our status as experts whose opinion can be trusted is threatened when treatment recommendations change or previously recommended treatments are proven harmful very quickly. Our deep desire to help should not cause us to abandon our need to analyze the evidence, continue learning, remain open but vigilant, and respect the scientific method.
Standards for Sharing and Adopting Experience and Ideas
The challenge posed by current ultra-rapid information sharing of COVID-19 information is similar to the challenges free open-access medical education (FOAM) has had to address. These include variable quality, differing peer review standards, anonymity, and forced brevity.3 Transparency regarding authorship, credentials, conflicts of interest, and potential biases are crucial, and active engagement between authors and readers can also be valuable.
When deluged with a wealth of information with a complex variability in quality of evidence, clinicians face a significant challenge in weighing the validity of evidence when making bedside decisions. If time allows (eg, a stable patient who is communicative and doing well), the evidence should be weighed to ensure safety and lack of undue adverse effects. For critical patients, compassionate or off label use of innovative therapies may be appropriate and may be based on a much lower level of evidence than traditionally expected for medical therapies.4-6
- When sharing experiences or innovations, clearly identify yourself, your credentials, and any conflicts of interest and potential biases—and commit to publicly revising or correcting what you have shared if new information changes its validity or safety.
- When adopting innovative practices or bringing novel, unproven therapies to the bedside, maintain a critical eye towards the quality of the evidence and guard against bias. Actively engage with colleagues in advance and, when time allows, directly with patients or surrogates about risks and benefits of unproven or innovative treatments.
- Be compassionate with yourself and with colleagues as you struggle to balance beneficence and non-maleficence in a time of dynamic change and unprecedented velocity of learning.
- Zagury-Orly I, Schwartzstein RM. Covid-19–A Reminder to Reason.N Engl J Med. 2020;383(3):e12.
- Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open. 2020;3(4):e208857.
- Allen, NG, ChandraSekaran EB, Goett RR, et al. We must analyze and clear up the ethical issues in FOAM. ACEP Now. 2018;37(11):24-25.
- Kalil AC. Treating COVID-19-off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA. 2020;323(19):1897-1898.
- Ladanie A, Ioannidis JPA, Stafford RS, et al. Off-label treatments were not consistently better or worse than approved drug treatments in randomized trials. J Clin Epidemiol. 2018;94:35-45.
- Xu X, Ong YK, Wang Y. Role of adjunctive treatment strategies in COVID-19 and a review of international and national clinical guidelines. Mil Med Res. 2020;7(1):22.