Bioethics Forum Essay
Clinical Trials vs. Right to Try: Ethical Use of Chloroquine for Covid-19
The president of the United States has famously touted the drugs chloroquine and hydroxychloroquine as potentially life-saving for Covid-19. They could be “one of the biggest game changers in the history of medicine,” he erroneously claimed. “So, it’s tested in the sense that you know it doesn’t kill you.” He has variously claimed it has “tremendous promise,” is “very effective,” and “can be taken safely.” His hyperbole hides the fact that chloroquine and its hydroxy variant have been around for a long time and have a reasonably safe record when used for other purposes, such a lupus and malaria prevention. I took chloroquine for two years while living in Nigeria from 1962 to1964 in the Peace Corps and didn’t think too much about it. There is also at least very preliminary report that a handful of Covid-19 patients may have benefited from the drug.
That being said, it has some risks. It can cause cardiac arrhythmias. According to the National Library of Medicine’s medlineplus.gov, it is associated with headache, nausea, loss of appetite, diarrhea, upset stomach, stomach pain, rash, itching, hair loss, seeing light flashes and streaks, blurred vision, reading or seeing difficulties (words disappear, seeing half an object, misty or foggy vision), difficulty hearing, ringing in ears, muscle weakness, drowsiness, vomiting, irregular heartbeats, convulsions, difficulty breathing, mood or mental changes, decreased consciousness or loss of consciousness, and thinking about harming or killing yourself, On the other hand, most of these effects are minor and rare. This leaves us with the question of whether the president, if sometimes muddled, over-enthusiastic, and just plain wrong about the drug, may nevertheless have a case to make. Should those suffering from Covid-19 or merely worried about being exposed have the right to use the drug?
I unqualifiedly accept the position that double-blind randomized clinical trials are the gold standard for answering the scientific question of whether a drug produces any effect, positive or negative, in Covid-19 patients. My training in research neuropharmacology leaves me biased in favor of insisting on such trials to answer the scientific questions.
There is a second, completely independent question to be addressed, however. It is the question of whether it is rational for a patient to choose to try a drug such as chloroquine for Covid-19 outside of a trial. Some patients may correctly hold that they have little to lose by trying it. Being killed by the drug might be seen as no worse or even better than weeks on a ventilator with a high probability of death (88%, according to one recent report). This question of individual patient self-interest is legitimate even if it leads to a different answer than the research question. It is sadly the case that sometimes trying the drug is in the rational interest of a patient who can’t wait for the results of a clinical trial.
To enter a subject into a randomized clinical trial ethically, the condition known as “equipoise” must be present. The concept of equipoise, first made well-known by a former Hastings Center intern, the late bioethicist Benjamin Freedman, incorporates the notion that there must be more or less indifference between the two arms of a randomized trial for a randomization to be ethical. There has been a lot of controversy over exactly who has to be more or less indifferent (i.e., “equally poised”) and how close to complete indifference must exist. The insight begins with the observation that if one were completely indifferent between two arms of a trial (between an active compound and a placebo, for instance), the only way one could choose between them would be by a flip of the coin. The theory of moral justification of randomized trials begins with the insight that, if one is completely indifferent and would flip a coin, there is no moral conflict between flipping the coin in a randomized trial and the interest of a patient. In early use of the concept of equipoise it was held that the research community must be at least relatively indifferent between the two treatment arms for a trial to be justified.
That justification ignored the possibility that an individual patient may be indifferent between treatment arms while researchers were not or—to consider the more problematic case—a patient may have a preference for one arm while researchers are legitimately and honestly indifferent. This is not a problem of patients being irrational. A patient may have a unique package of values that would lead him or her to prefer one of the treatment arms while researchers, with their values, really are indifferent. It is possible for a patient to correctly perceive an advantage from an experimental agent even if most researchers believe there is no net advantage from the experimental agent compared to a placebo. For him or her, the treatment is rationally linked to the preferred outcome. For instance, a patient may be terribly risk-averse and want to avoid the experimental treatment arm while researchers with more typical risk aversion consider the risks to just about equal the potential benefits. That patient today has the absolute right to get what he or she prefers (by refusing to consent to being in the trial), and it is reasonable for him or her to refuse the offer to be randomized.
On the other hand, another patient may aggressively value taking the risks of the experimental treatment; he or she may say that life isn’t worth living unless I am cured of my condition or that without the experimental agent my future would be so terrible that it is worth taking the risk of the new drug, For such a person, access to the experimental treatment is rationally in his or her interest. The patient would rather die from the experimental agent than live in the condition that will result without the drug.
At such a point, where the patient has a rational preference for the treatment while the researchers are legitimately indifferent, there is a conflict between answering the research question in the best way possible and the right of the patient to try something that really is in his or her interest.
This could be the unfortunate situation we find ourselves in with chloroquine and hydroxychloroquine. It is misleading, indeed false, to say that a patient has nothing to lose by trying the drugs or that they can’t kill someone with Covid-19 just because they almost never kill people with lupus or those trying to avoid malaria. On the other hand, it may well be true that the risks of not using one of the chloroquines are greater for some Covid-19 patients than the risks of using it. That was particularly true in the early weeks of the chloroquine discussion when we had some very tentative evidence that it may have helped a handful of patients and had not harmed any of them. The benefit-harm calculus to a given patient changes daily as a result of new drug information and his or her disease progression. The patient facing the decision to go onto a ventilator in the days when evidence of harm was lacking might have plausibly looked favorably on chloroquine. On the other hand, recent reports from a nonrandomized clinical trial of hydroxychloroquine suggesting that those getting it had higher mortality than those who did not could change the calculation in the other direction. With some sets of daily-changing facts, it may be rational for a patient to prefer the risks of chloroquine while at the same time the research question can best be answered by a randomized trial.
At this point we have two options: 1) require that patients only get access to the drug through a randomized, carefully controlled trial, thus riding roughshod over the rational interest of some patients in trying the drug or 2) permit patients to choose the course they prefer based on their values (including the option of permitting those who rationally prefer the drug to have access to it). If we are clever, however, we might be able to satisfy both goals at the same time,
The conservative patient who prefers not to risk taking the drug until it is proven effective for Covid-19 has the absolute right to his or her preference. Once we realize that it is logically possible for a patient to prefer the unproven drug, we could also give that patient access. If we are nimble in our planning, there will be a time when researchers are legitimately indifferent between the drug arm and the placebo arm It is plausible that some patients are likewise indifferent. We can do the randomized trial using those patients who are close enough to being indifferent that they don’t mind flipping a coin.
We can, with moral justification, complete a clinical trial even after researchers begin to have a preference for one of the arms if we realize that, at least for a while, some atypical patients may drift into indifference while other patients and researchers begin to have a preference for one of the arms. A month or so ago, when there were rumors of possible benefit of hydroxychloroquine with scant evidence of serious harms, some conservative patients might nevertheless have preferred not trying the drug while some slightly less conservative patients might have been indifferent to whether they got the drug or not. The latter patients could ethically have been randomized. Meanwhile some patients more willing to take risks might have preferred trying the drug and should have had a right to get it.
A day before this writing, an unpublished report leaked that a Veterans Affairs study was finding no benefit and possible higher mortality in the group getting hydroxychloroqine. That information might make some patients change their minds. Patients who would previously have preferred the drug to a placebo might become indifferent and willing to be randomized; somewhat conservative patients who would have previously been willing to be randomized might now refuse to enter the trial.
In the end, whether hydroxychloroquine is beneficial or harmful depends not only on the results of trials, but also on the unique value systems of individual patients. It is those patients who are close enough to indifference that they are willing to be randomized who permit us to ethically answer the science question. If we do it right, we can answer the science question while simultaneously recognizing the right of patients to choose the therapeutic strategy that will best fit their idiosyncratic values. Those who prefer the standard (nonchloroquine) treatment already have the right to get it. Those who prefer the chloroquine should get it as well (at least as long as granting access does not deprive those who need the drug for more traditional accepted uses). The patients who are ambivalent about getting chloroquine can ethically be randomized. As long as there is an open question in the scientific community about whether chloroquine or its hydroxy variant helps patients with Covid-19, there should be patients close enough to indifference that they are willing to volunteer to be randomized. Especially at the present moment, there should be plenty of patients in all three categories. We can simultaneously honor patients’ preferences and do gold standard research.
Robert M. Veatch, PhD., is Professor of Medical Ethics Emeritus and Senior Research Scholar at the Kennedy Institute of Ethics, Georgetown University. A Hastings Center fellow, he was the associate for medical ethics and then senior associate at The Hastings Center from 1970 to 1979. Twitter: @veatchr
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