Facing an emergent pathogen without effective treatment, clinicians were desperate to save their COVID-19 patients. Some repurposed drugs previously approved for other indications. Others experimented with interventions postulated to work by physiological reasoning or clinical experience in similar scenarios. Unfortunately, numerous heroic efforts turned out to be ineffective. Some drugs (e.g., hydroxychloroquine) even proved harmful.
We learned that the understandable desire to help individual patients in a crisis, instead of initiating placebo-controlled randomized trials, can impede the scientific evaluation of urgently needed potential therapies. The Covid-19 pandemic made the predicament of having to choose between initiating treatment with an unproven intervention or launching a rigorous study of its safety and efficacy a glaring and urgent ethical issue.
In 2020, in a departure from its usual approval process, the FDA issued an Emergency Use Authorization decision for COVID-19, allowing wide use of a number of untested therapies, bypassing further research. These actions by the FDA raised an issue that has been largely unaddressed by current research ethics guidance. For the most part, existing ethical guidance for research prioritize protecting participants. Regulators’ guidance takes a one-size-fits-all approach, and the rules they issue for assessing risks of harm and potential benefits are vague. Yet, there are tremendous differences in the conditions that require new or improved treatment, the circumstances in which they arise, and the kinds of treatment that require study. Some conditions are mild with minimal effects on the quality of life (e.g., toenail fungus), but others have devastating effects and are life threatening. Some short-lived diseases have minor consequences (e.g., the common cold), others can have serious long-lasting effects (e.g., polio) or unknown long-term effects (e.g., COVID-19). Some diseases are chronic with life-altering consequences (e.g., diabetes, allergies). Some diseases progress slowly, others rapidly, some affect millions of people, others affect just a few. These radical differences raise ethical questions about whether factors such as urgency, prognosis, the number of people affected, or uncertainty require different responses, and whether ethical guidance should be more nuanced and specific to the circumstances.
When the COVID-19 pandemic raged all over the globe, it overwhelmed hospital resources. Clinicians and researchers became painfully aware that standard directions for balancing risks and benefits do not address an array of issues that clinicians and researchers had to confront during the devastating outbreak. Decision makers were concerned about what might happen to patients who were not offered untested treatments. They asked themselves if they were justified in offering “treatments” that had not been proven safe and effective for the disease. They agonized over whether the speed of finding a safe and effective treatment justified undertaking a randomized placebo-controlled trial while their patients were critically ill and fighting to survive.
This panel will address two critical issues faced by clinicians confronting patients with devastating disease when no proven treatments are available. (1) Should they offer unstudied interventions as innovative treatment in the face of a novel and devastating disease or immediately initiate clinical research? (2) Should they consider the seriousness of the disease and the extent of its effects on the population as relevant factors in their decisions? Specifically, panelists will address the question of whether the requirements for offering an unproven intervention as treatment should be different from standards for initiating research. They will also address the question of who should be enrolled in studies, those most or least vulnerable to devastating effects of the disease or those most or least likely to suffer serious or enduring complications. Although there have been repeated calls for a normative and empirical analysis of how innovation and research for devastating disease should be integrated, these issues remain unresolved.
Medical professionals confronted analogous issues during the AIDS epidemic, and clinicians who treat patients with devastating diseases such as Alzheimer, Amyotrophic Lateral Sclerosis, and childhood cancer continue to grapple with similar dilemmas. Because conflict between initiating innovative treatment and prioritizing rigorous research is a persistent issue, what we learn from this discussion will be applicable to other situations in which medical professionals have to make similarly challenging decisions.
Panelist from different professions, different institutions, and different countries will share their COVID-19 pandemic experiences and the insights they have gleaned on both issues. Their different perspectives will reflect both support and criticism for what was done as the pandemic raged. Panelist presentations will aim at developing an understanding of medicine’s professional responsibilities to patients and society. The panel presentations and the ensuing discussion may help provide guidance for the next time we find ourselves in such dire straits.
Each panelist will begin by sharing personal experiences of being involved in decisions about whether to offer unstudied interventions as treatment or launch rigorous research during the peak of the COVID-19 pandemic. They will then offer their recommendations and their reasons for reaching those conclusions on (1) prioritizing innovative treatment or rigorous research and (2) if and how the extraordinary circumstances may have justified deviation from standard rules of research ethics and medical care.
Format of Symposium:
Each presenter will speak for 12 minutes leaving 30 minutes for questions from the audience and panelist replies. (90 minutes total).
COVID Treatment and Research: A Perspective from New York City
Professor Henry Sacks | Icahn School of Medicine at Mount Sinai | United States
An infectious disease specialist and clinical researcher will discuss the impact of COVID-19 in New York City in the early days of the pandemic, when hospitals were overwhelmed with extremely ill sick patients. During the peak of the pandemic in the spring of 2020, the integrated Mount Sinai Health System had over 2,000 inpatients and had to expand its intensive care units and open a tent hospital in Central Park. Clinicians had little information on how to treat their extremely ill patients. The panelist will compare the COVID-19 experience with the early days of the HIV pandemic, which also disproportionately affected New York City. During both crises, clinicians and clinical researchers confronted the tension between trying to save the lives of desperately ill patients and the need to determine which treatments actually worked. The reflections on working within the constraints of the US political climate and its health care system may offer useful lessons for future pandemics. In particular, the panelist will reflect on the effect of widespread emergency use authorization, (the permission to administer unproven drugs for a disease without known effective treatment) on the rather limited conduct of rigorous clinical research in the USA on COVID-19 therapies.
A Perspective on COVID Treatment and Research from Wales, UK
Dr. Victoria Shepherd | University Hospital of Wales | United Kingdom
A researcher based in a clinical trials unit Wales, where his/her team designs and conducts clinical trials, will describe how the British National Health Service integrates research into patient care pathways. The panelist will outline UK research ethics governance structures and how they were modified early in the pandemic. (S)he will also discuss the RECOVERY trial, which involved patients critically ill with COVID-19. In that study, decisions about participation relied on consent from surrogate decision-makers. The presenter will share new study findings on how surrogates viewed the benefits and risks of participation. The experiences of conducting trials, such as RECOVERY, and the understanding gained from studies of surrogate consent to research brings lessons for trials in similar contexts both during and beyond pandemics.
A Perspective on COVID Treatment and Research from Oxford, UK
Dr. Mark Sheehan | Ethox Center | United Kingdom
A senior ethics researcher and philosopher, serving on the several UK National Research Ethics Boards will shine light on the distinctive research and clinical frameworks that exists in Oxford and the UK. This unique setting, and more significantly, the established infrastructure, provided an important catalyst for the RECOVERY study and other large clinical trials during the pandemic. (S)he will consider some of the ethical issues which arise from the close proximity of research and clinical settings. He will suggest that these issues, particularly those connected to decisions about whether to offer research participation to a particular patient, are not materially different from the usual kinds of decisions that clinicians must make. Given the benefits that well-conducted research can bring to medical practice, he will argue that there is a strong ethical imperative for close institutional integration of large-scale research and clinical practice.
4) A perspective on unstudied treatment and research in critical care from Romania
Associate Professor Cristina Petrisor | "Iuliu Hatieganu" University of Medicine and Pharmacy Cluj-Napoca | Romania
An anesthesia and intensive care physician will relate the personal experience of providing care for patients with COVID-19 in an overwhelmed and understaffed ICU during the pandemic peak in Romania. At one point, clinicians were required to provide hydroxychloroquine as treatment and later learned that it was not only ineffective as a treatment for the disease, but possibly counter-productive. (S)he and his/her team conducted a study of treatment for COVID patients with anemia and participated in the ESICM UNITE study, a large multicenter project with COVID patients that developed an ultrasound algorithm for COVID monitoring. In addition, (s)he conducted a study with critical care nurses on their experiences and moral distress from providing treatment and conducting research in the ICU during the pandemic. The panelist will discuss the ethical issues (s)he encountered during COVID studies such as study enrolment of hypoxic, sedated, or comatose intubated patients and the reliance on surrogate consent. She will also share his/her views on the necessity of rapidly conducting studies to gain reliable data.
A Perspective on COVID Treatment and Research from Jerusalem, Israel
Dr. Moshe Greenberger | Shaare Zedek Medical Center | Israel
An Israeli physician will share his extensive experience with treating COVID-19 patients in both hospital and home environments, and first-hand experience with addressing dilemmas associated with treating rapidly deteriorating, critically ill patients during the first wave of the COVID-19 pandemic, when little or no information regarding the efficacy of proposed empirical treatments was available. This physician will compare that initial experience with subsequent waves of the pandemic when more evidence-based treatments became available. (S)he will also share experiences from a palliative care standpoint, relating to end of life issues unique to an isolated hospital ward. An Israeli bioethicist will relate the ethical challenges inherent in these settings to the religious approaches prevalent in Israel (primarily Jewish but also Islamic) in which immediate lifesaving has traditionally been given much higher priority than research with potential for future remedies.