“There’s no proof that anything works!” The ethics of COVID-19 research

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This post is a part of our Bioethics in the News seriesBioethics in the News purple and teal icon

By Robyn Bluhm, PhD

The New York Times Magazine recently published a long-form story about the tension between treating patients with COVID-19 by any means that might improve their chances of survival and recovery, and enrolling them in clinical trials to establish the safety and efficacy of these treatments, thus improving care both for future patients and for those who survived the trial. As with many stories about health care in the current pandemic, this article both raises perennial issues in bioethics and shows them in their starkest form: the seriousness of the condition of these patients and the lack of knowledge about how best to help them mean that the ethical dilemma described in the story is particularly clear. But a closer look at work in bioethics and the epistemology of clinical research suggests that, while the dilemma is clear, there are more ways forward than the two incompatible ways portrayed in the story.

The story begins by describing the clash between a critical-care physician faced with a COVID-19 patient whose condition was worsening, and a researcher who had enrolled that patient in a clinical trial. The former wanted to give the patient a higher-than-standard dose of the anticoagulant she was being treated with, even though this might mean that she would need to be withdrawn from the trial. The latter advocated for the importance of maintaining the integrity of the study, saying that acting on instinct instead of on evidence “was essentially ‘witchcraft’.”

Unsurprisingly, this characterization did not go over well with the other doctors in the meeting. A less contentious way of describing the situation might have been to say that, while doctors use their clinical judgment to make decisions about how best to use available evidence in caring for a particular patient, this only works when there is evidence available. And everyone agrees that, in the case of COVID-19, there is horrifyingly little evidence. This means that enrolling COVID-19 patients in clinical trials is not depriving them of standard care (care that such patients would ordinarily receive if not in the trial)–standard care for this condition does not yet exist.

Nurse with medical equipment illustrated image
Image description: An illustration of a health care worker wearing blue scrubs, head covering, and face covering. Surrounding them are a stethoscope, face mask, syringe and surgical tools, thermometer, and microscope. The background is light pink. Image source: sunshine-91/Vecteezy.

There is a lot to think about here. Importantly, it’s not the case that the doctors treating seriously ill patients had no idea what to do. They had a wealth of experience treating patients with severe viral infections, with acute respiratory distress syndrome, with cardiac arrest, or with pathological immune reactions (the “cytokine storm” sometimes seen in chemotherapy patients). Some of this knowledge informed the care of early COVID-19 patients, raising the question of which treatments could be successfully generalized to this new patient group.

The notion of generalizable knowledge is in fact central to research ethics. The Belmont Report, which guides research ethics oversight in the United States, draws a bright line between research and clinical practice on the basis of their ostensibly distinct goals. Research aims to provide generalizable knowledge, while clinical practice aims to benefit an individual patient. This way of drawing the distinction meant that when physicians depart from standardly-accepted care in the treatment of an individual patient, it does not count as research (and therefore does not require ethics review). It also leads to the problem described above: enrolling a patient in a research study requires that they forgo their right to individualized care and are treated according to study protocol. Deviations from the protocol, such as the one described in the opening of the New York Times story, are prohibited. Patients whose care does not follow the protocol will usually be withdrawn from the study.

But this sharp distinction between research and practice also makes assumptions about the kind of clinical research being conducted. Schwartz and Lellouch (1967) distinguish between “explanatory” and “pragmatic” approaches to clinical trials. Explanatory trials are designed to minimize the influence of any factors, other than the experimental therapy, that could affect the outcome being measured. These other factors include additional medications and the presence of comorbid disease. Pragmatic trials, by context, are designed to resemble actual clinical practice, where patients often take more than one medication and often have more than one health problem. Pragmatic trials may also enroll a wider variety of participants (especially older participants), permit alterations in the study protocol, be more flexible in the timing of outcome measurement; in general, they are more flexible in their design and analysis. A given trial will fall somewhere on the spectrum between “highly explanatory” and “highly pragmatic” in its design.

In the case of COVID-19, there are good reasons to favor trials that are more pragmatic. First, there are so many factors that might affect prognosis (or were previously thought to do so) – age, gender, weight, blood type, various pre-existing conditions – that the study population cannot be narrowly defined. If it is, then the results of the study will apply only to people in that narrow population. Second, care for critically ill patients is rapidly developing. Even in the absence of an established drug regimen, survival rates have been improving. This means that by the time a trial is completed, the experimental therapy will be implemented in a very different context of care. Perhaps more importantly, because of these first two reasons, a strict, explanatory trial is less likely to give generalizable knowledge than a more pragmatic one (Bluhm and Borgerson, 2018). Research that reflects clinical practice is more likely to be useful in improving clinical practice.

Robyn Bluhm photoRobyn Bluhm, PhD, is an Associate Professor with a joint appointment in the Department of Philosophy and Lyman Briggs College at Michigan State University. She is a co-editor of The Bloomsbury Companion to Philosophy of Psychiatry.

Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Thursday, September 3, 2020. With your participation, we hope to create discussions rich with insights from diverse perspectives.

You must provide your name and email address to leave a comment. Your email address will not be made public.

More Bioethics in the News from Dr. Bluhm: Philosophy, Mental Illness, and Mass Shootings; “Ask your doctor” – or just check Instagram?Antibiotics: No Clear CourseTo Floss or Not to Floss? That’s not the question

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Listen: Activating and Empowering Patients

No Easy Answers in Bioethics logoNo Easy Answers in Bioethics Episode 15

How can shared decision-making tools and evidence-based guidelines be used to ensure that every patient receives the best care possible? How can patients be activated and equipped to interact with their provider and manage their health condition? In this episode, three Michigan State University researchers—Dr. Bill Hart-Davidson, Professor in the Department of Writing, Rhetoric, and American Cultures, Dr. Karen Kelly-Blake, Assistant Professor in the Center for Ethics and Humanities in the Life Sciences and the Department of Medicine, and Dr. Ade Olomu, Professor of Medicine in the Department of Medicine—discuss a shared decision-making tool they developed called Office-GAP, Office-Guidelines Applied to Practice. Together they discuss the origins of the project, and the results so far in improving outcomes for patients managing chronic illness by using a simple checklist to get patients and providers on the same page.

Ways to Listen

This episode was produced and edited by Liz McDaniel in the Center for Ethics. Music: “While We Walk (2004)” by Antony Raijekov via Free Music Archive, licensed under a Attribution-NonCommercial-ShareAlike License. Full episode transcript available.

About: No Easy Answers in Bioethics is a podcast series from the Center for Ethics and Humanities in the Life Sciences in the Michigan State University College of Human Medicine. Each month Center for Ethics faculty and their collaborators discuss their ongoing work and research across many areas of bioethics. Episodes are hosted by H-Net: Humanities and Social Sciences Online.

Antibiotics: No Clear Course

Bioethics in the News logoThis post is a part of our Bioethics in the News series

By Robyn Bluhm, PhD

It’s something we’ve all been told: be sure to finish taking your antibiotic prescription. Don’t just stop when you begin to feel better. Doing so, we’re warned, may mean that the bacteria causing the infection have not been completely eradicated. Once treatment stops, they will begin to multiply again, causing a relapse. Worse, it may result in the development of antibiotic-resistant bacteria, which is dangerous both to the individual taking the medication and to the public as a whole.

But a recent article in The BMJ argues against this common wisdom, saying that advice to “complete the course” is not evidence-based—and that doing so may actually have the opposite effect of increasing, rather than decreasing, the risk of antibiotic resistance.

antibiotics package photo
Image description: a pack of antibiotics with a green arrow pointing toward “Your first day’s dose”–two pills are missing and four remain unopened. Image source: Joseph Nicolia/Flickr Creative Commons

I find this piece—and reactions to it in on the journal’s website—interesting for bioethics because it illuminates the complex relationship between evidence and patient care. The article recommends changing treatment practices because of evidence that they may do more harm than good, but doesn’t really have a plan for what to change them to. This conundrum leads the authors of the article to make some interesting, but incomplete, suggestions related to physician-patient communication and shared decision-making. The commentaries on the paper challenge both the authors’ claims about the available evidence and their suggestions about sharing doubts about current practice with patients.

Changing Clinical Practice?
The randomized controlled trial (RCT) is currently thought to be the “gold standard” of evidence in medicine. It is not uncommon for discussions of medical evidence to cite examples of treatments that were in common use before an RCT was conducted, that were then shown by the trial to be useless or even harmful. This time last year, I blogged about a report that suggested that there is no evidence that flossing your teeth has any benefits. In response to this report, a number of people suggested that we should just stop flossing. In the late 1980s, a large RCT showed that two drugs commonly used to treat arrhythmia actually increase the risk of cardiac death and the authors recommended that their use be discontinued.

The question addressed in the BMJ paper is more complex than either of these cases. The recommendation is not to stop using antibiotics altogether, but to change the way that they are used. And the recommendation is not based on RCTs, but on the lack of evidence for current practice; on the flawed reasoning that linked early discontinuation with antibiotic resistance; and on evidence that overuse of antibiotics is actually the most important causal factor in the development of resistance. The authors identify only seven conditions for which researchers have conducted RCTs that directly compared a shorter with a longer course of treatment. Moreover, even in cases where the shortest effective course of an antibiotic treatment for a health condition has been identified, it’s not possible to extrapolate from this situation to the use of other antibiotics, or the use of that antibiotic for other diseases.

The authors of the BMJ paper do emphasize that more evidence is needed. But until that research has been done (if it ever is done), it’s not clear how doctors should change their current prescribing habits. As the discussion in the article makes clear, the answer to this question will depend on a number of factors, including the kind of infection and the specific antibiotic being used. Moreover, it will depend on the individual patient, as “patients may respond differently to the same antibiotic, depending on diverse patient and disease factors” (p. 2).

Talking with Patients
Given the number of factors that might affect patient outcomes, it would not be surprising if the authors of the article were unwilling to make specific recommendations for clinical practice. In fact, they don’t make a recommendation in terms of what doctors should prescribe for their patients. Instead, they end their paper with a section titled “How should we advise patients?” While prescribing a medication regimen certainly counts as giving a patient advice (at least implicitly), they couch their discussion in terms of general communication strategies, rather than of specific practice guidelines. In this section of the paper, they suggest that part of the reason that the traditional advice to “complete the course” has been so resilient is that “it is simple and unambiguous, and the behavior it advocates is clearly defined and easy to carry out” (p. 3). In addition to recommending further research on the appropriate dose of antibiotic, the authors also recommend research to identify “the most appropriate simple alternative messages” (p. 3). One possibility is to tell patients to stop when they feel better–exactly the opposite of what we have generally been told. More immediately, however, they say that doctors should begin to educate patients about the problems with the traditional advice, telling them that antibiotic overuse is the real problem that leads to antibiotic resistance. They suggest that honesty about our current lack of knowledge is better than “simply substituting subtle alternatives” such as the instruction to “take exactly as prescribed” (p. 3).

Take as directed…
A number of the commentaries on the BMJ website express frustration with the article–and with the situation it describes. Some of the commentaries emphasize that the article title is misleading or that the article itself overstates the conclusion that can be drawn based on the available evidence. Others worry that patients will take this article (and the media coverage that suggests that they should stop taking their antibiotics when they feel better) as license to ignore their doctor’s recommendations. One commenter even suggests that patient-centered decision-making is dangerous, and an illusion, when there is still medical debate on a topic. Yet many also agree that there is a problem with current practice.

The problem is that, if Llewelyn et al. are even close to correct, there is no clear direction for physicians or for patients. Confusingly, this seems like a case in which the growing evidence leave us knowing less, rather than more.

Robyn Bluhm photoRobyn Bluhm, PhD, is an Associate Professor in the Department of Philosophy and Lyman Briggs College at Michigan State University.

Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Thursday, September 7, 2017. With your participation, we hope to create discussions rich with insights from diverse perspectives.

You must provide your name and email address to leave a comment. Your email address will not be made public.

Note: some articles linked in this commentary may require MSU Library or other institutional access to view the full text.

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The 2014-15 Bioethics Brownbag & Webinar series kicks off with a discussion on ‘Designing for Diffusion’

bbag-icon-decDesigning for Diffusion and Ethical Considerations

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Designing for Diffusion (D4D) means taking certain steps early in the process of innovation planning to heighten the likelihood of awareness, information seeking and advice seeking, trial adoption, and then effective implementation and sustained use of evidence-based practices, programs and policies. Are there ethical boundaries in designing for diffusion of health system innovations? The present talk will outline the components of this approach and then raise ethical considerations of such intervention, for discussion.

sept-17-bbagJoin us for James W. Dearing’s lecture on Wednesday, September 17, 2014 from noon till 1 pm in person or online:

In person: The lecture will take place in C102 East Fee Hall on MSU’s East Lansing campus. Feel free to bring your lunch! Beverages and light snacks will be provided.

Online: Here are some instructions for your first time joining the webinar, or if you have attended or viewed them before, go to the meeting!

Can’t make it? View this webinar and others as archived recordings.

Jim Dearing (PhD, University of Southern California) studies and practices the diffusion of innovations.  He studied under and collaborated with Everett M. Rogers for 20 years. Jim has led research projects funded by the U.S. National Cancer Institute, the National Science Foundation, the Agency for Healthcare Policy Research, the Centers for Disease Control and Prevention, and private foundations including the John D. And Catherine T. MacArthur Foundation, the Robert Wood Johnson Foundation, the W.K. Kellogg Foundation, and the Bill & Melinda Gates Foundation. Jim is a Professor and Chairperson in the Department of Communication Michigan State University.