Tag: clinical trial

“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dose of the anticoagulant she was being treated with, even though this might mean that she would need to be withdrawn from the trial.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.

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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.

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

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HIV prevention: benefits, barriers, and ethical concerns

bbag-icon-decEthical Implications of HIV Pre-Exposure Prophylaxis (PrEP) for African American Women and Adolescent Girls

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Pre Exposure Prophylaxis (PrEP) is a new HIV prevention strategy approved by the Food and Drug Administration for use by uninfected, high-risk adult populations. PrEP’s potential as an HIV preventive strategy/biomedical method for adolescents is unknown. The presentation will present preliminary results from a study that examined benefits, barriers, and ethical concerns associated with Pre-exposure Prophylaxis (PrEP) utilization and clinical trial participation among African American adolescent girls. Study findings have the potential to generate evidence-based data to inform HIV research ethics practices and increase just and fair access to HIV scientific advances.

feb-17-bbagJoin us for Faith Fletcher’s lecture on Wednesday, February 17, 2016 from noon till 1 pm in person or online.

Faith E. Fletcher is an Assistant Professor in the Division of Community Health Sciences at the University of Illinois at Chicago (UIC). Prior to joining UIC faculty in 2013, Dr. Fletcher completed a National Cancer Institute R25T- funded postdoctoral fellowship in the Department of Behavioral Science at the University of Texas MD Anderson Cancer Center. The ultimate goal of her research program is to address HIV-related health inequities by understanding barriers that prevent African American women and adolescent girls from accessing innovative HIV preventive methods and treatment. Recent awards include joint funding through the Developmental Center for AIDS Research and Center for Clinical and Translational Science; Kaiser Permanente Burch Minority Leadership Fellowship; Building Interdisciplinary Careers in Women’s Health Research (BIRCWH K12) Fellowship; Visiting Professor in Minority Health through Northwestern Feinberg School of Medicine’s Program in Public Health; and an HIV Research Ethics Training Institute (RETI) Fellowship through Fordham University’s Center for Ethics Education. Dr. Fletcher received her foundation in bioethics and social justice through Tuskegee University’s National Center for Bioethics in Research and Health Care and Michigan State University’s Interdisciplinary Program in Bioethics, Humanities and Society. She completed her PhD in Health Behavior and Promotion from the University of South Carolina Arnold School of Public Health in 2011.

In person: This 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? All webinars are recorded! View our archive of recorded lectures.

The Joshua Hardy Case: Lessons Yet to Learn

Bioethics-in-the-News-logoThis post is a part of our Bioethics in the News series. For more information, click here.

By Hannah Giunta

Earlier this month, major news outlets reported the story of 7-year-old Josh Hardy, a current end-stage cancer patient at St. Jude Children’s Research Hospital. Hardy has faced and overcome cancer four times after first being diagnosed with rhabdoid tumors of his kidneys when he was only nine months old. After treatment for his kidney cancer, he relapsed, and cancer was again found first in his thalamus and then in his lung. In November 2013, Josh was diagnosed with myelodysplastic syndrome and required a bone marrow transplant. The weakening of his immune system caused him to come down with a particularly vicious case of adenovirus, and current antivirals have failed to control that infection. After approved drugs failed, Hardy’s doctors suggested that the experimental agent brincidofovir might offer the only viable chance at a cure. St. Jude previously hosted a clinical trial where patients who received the drug demonstrated a decrease in adenovirus-specific viral load. Hardy’s parents petitioned manufacturer Chimerix to provide the drug through a compassionate use protocol, but the company refused, saying that giving the drug to Josh and other critically ill patients would likely slow down the drug’s approval process. Chimerix officials also explained that the drug had not been proven effective in advanced adenovirus cases like Josh’s and that they did not have a current clinical trial in which they could enroll Josh. Public outcry over Chimerix’s refusal of the request, which included death threats directed at company executives, eventually pushed Chimerix to reconsider its decision and work with the FDA to start a new clinical trial in which Josh could enroll.

Although Josh Hardy’s case has been uneasily resolved, at least for the time being, public reaction reveals that larger questions are still unanswered. First and foremost, we continue to struggle with distinguishing our research system from our clinical care system in the U.S., and the resulting therapeutic misconception causes dashed dreams and animosity between drug developers and well-meaning, though misinformed, patient advocates. The truth is that the medication Josh is receiving out of compassion may make his life worse in the end, and failure to recognize this reality means false hope for families and insufficient attention paid to Josh’s quality of life. Secondly, there is a conflict between the needs of current patients like Josh and the needs of future patients who will benefit most from a fully approved medication. That conflict can only be meaningfully resolved when we have an honest discussion about what compromises we are willing to make. We cannot have both a drug development system that releases cutting edge medications meeting our stringent safety standards efficiently and one that makes unproven medications available on demand. The clinical trial system is not designed to release experimental agents for public consumption, even when that consumption occurs according to compassionate use protocols. Failing to get to the bottom of these conflicts leads to unnecessary heartache and public outrage.

Philosophers, researchers, and clinicians have struggled for years with how to prevent and ameliorate the impact of the therapeutic misconception. Defined as the failure to appropriately distinguish between the goals of research and the goals of clinical care, the therapeutic misconception leads to patients and family members believing that clinical trials are actually cutting edge treatment options, rather than legitimate experiments designed primarily to yield generalizable knowledge. In an effort to maintain hope for current patients, clinicians recruit participants with end-stage disease in order to push a research agenda forward while anecdotally hoping that somehow the experimental agent might benefit the enrollees. Unfortunately, previous reviews of pediatric cancer protocols suggest that substantial survival time is relatively rare. In fact, significant survival time was actually less common than drug-related toxicity (Kim et al. 2008). In Josh Hardy’s case, brincidofovir has only been shown to be effective in patients who did not have advanced adenovirus infection. Even then, the drug only demonstrated the ability to decrease viral load, and with Josh’s weakened immune system, his body may still not be able to clear the infection. Tissue damage is likely already significant after two months of illness. Most importantly, Josh has other significant co-morbidities and has had multiple cancer relapses. After Josh received his first dose of the drug, his own father admitted that his son faces a long road and is in bad shape overall (Cohen 2014). Seeing Josh weak, frail, and seemingly miserable in his hospital bed should leave us wondering whether this little boy has suffered enough. Perhaps, he might be better off if we focused solely on palliation and allowed the time he has left to be more comfortable and meaningful for him and his family.

The unique goals of medical research stem largely from a need to standardize clinical trials as much as possible to meet FDA standards. In order to show efficacy and safety, researchers use the gold standard double-blind, placebo-controlled clinical trial design. While this design helps researchers show aggregate differences in outcomes, it makes it less likely that individual patients will benefit from trial enrollment. In the trial earliest stages, participants are often randomly assigned to dosage groups, meaning that some participants may not even be receiving a therapeutic dose. In subsequent phases, participants are still randomly assigned to treatment arms of the trial, and if clinician-researchers don’t know what treatment a participant is receiving, it’s unlikely that they can provide individualized medical care for their patients. Living up to the FDA approval system’s high scientific requirements is a reality for Chimerix and other pharmaceutical companies, so distributing a drug in a less controlled situation presents a conflict. Maybe it is time to consider whether or not more novel trial designs or blended designs where patients receive an experimental intervention in a less controlled setting might help address this problem. Pediatric oncologists have recently expressed this opinion in a major research journal (Kearns and Morland 2014). Until we decide how rigorous our drug review standards need to be, we are forcing companies to confront a constant conflict between the human need for compassion and the larger social goal of developing new treatments.

Josh Hardy may or may not survive his current illness, although I hope and pray that he prevails. But, no matter the outcome, the Josh Hardy case should not be the end of our discussion. Josh’s story should push us toward a national conversation that asks the big questions. Most importantly, it requires us to reconsider the popular notion that research can serve two masters (i.e. the public and current patients) as well as the idea that length of life ought always to be our barometer for ultimate success in the face of terminal illness.

References:

Cohen, Elizabeth. “Josh Hardy’s father says son faces ‘long road to recovery.’” 15 Mar 2014. Last accessed on 3/17/2014 at http://www.ksl.com/?sid=29075987&nid=157.

Kearns P, Morland B. New drug development in childhood cancer. Curr Opin Pediatr. 2014 Feb;26(1):37-42. doi: 10.1097/MOP.0000000000000054. PubMed PMID: 24362409.

Kim A, Fox E, Warren K, Blaney SM, Berg SL, Adamson PC, Libucha M, Byrley E, Balis FM, Widemann BC. Characteristics and outcome of pediatric patients enrolled in phase I oncology trials. Oncologist. 2008 Jun;13(6):679-89. doi: 10.1634/theoncologist.2008-0046. PubMed PMID: 18586923.

Lupkin, Sydney. “Dying Boy to Get Unapproved Drug After Family’s Plea.” 12 Mar 2014. Last accessed on 16 Mar 2014 at http://abcnews.go.com/Health/dying-boy-unapproved-drug-familys-plea/story?id=22873957.

Lupkin, Sydney.  “Family Petitions For Unapproved Drug To Save Son.” 11 Mar 2014. Last accessed on 16 Mar 2014 at http://abcnews.go.com/Health/family-petitions-unapproved-drug-save-son/story?id=22851791&singlePage=true. 


hannah-giunta-100Hannah Giunta is a fifth year DO-PhD student pursuing a PhD in Philosophy and Bioethics.

Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Thursday, April 3, 2014. 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.

SUPPORTING Research Ethics: The Odds and the Outcomes

Bioethics-in-the-News-logoThis post is a part of our Bioethics in the News series. For more information, click here.

By James L Nelson, PhD

Quite some time ago as breaking news is measured—back on April 10th—the New York Times printed a story(1) on the Office of Human Research Protection’s (OHRP) official response to a five year, multi-center study: the Surfactant, Positive Pressure, and Oxygenation Randomized Trial, aka SUPPORT. In an effort to refine guidelines for the use of oxygen for premature infants, SUPPORT enrolled 1316 infants born at between 24 and 27 weeks of gestational age and randomized them to one of two treatment protocols. Contemporary practice was only weakly guided by data, but had generally settled on maintaining blood oxygen levels at levels ranging from 85-95%; just where in that range had been determined as much by clinical intuition as anything else. The children in the study were to be maintained within either an 85-89% blood oxygen range, or within a 91-95% level; the hope was to determine whether practice might become more precise.

The results, as reported in The New England Journal of Medicine(2) were somewhat surprising to clinicians. More of the children randomized to the lower level died—19.9%, contrasted with 16.2% in the higher group. On the other hand, the group maintained at 91-95% experienced a higher incidence of severe retinopathy—17.9, contrasted with 8.6. Perhaps an even bigger surprise was the letter OHRP wrote to the study organizers. OHRP found that the informed consent documents used in the study were deficient. Parents were not properly informed that that their children’s risk of death or damage could be affected by their participation in the study.

The Editorial Board of the Times called the informed consent lapse “startling and deplorable”(3), and in an entry on the Albert Einstein College of Medicine blog dated April 18, Ruth Macklin claimed “there is no doubt that the consent forms in this study of premature newborns failed to disclose what these parents should have been told before enrolling their infants in the research”(4). But at least some of the researchers involved in the study have made it clear that they’re doubtful about that, to say no more. In a reply to the Times editorial, three SUPPORT investigators claimed that there was no reason to list an increased risk of death as a risk of participation in the study, as “the best evidence showed that lower oxygen targets…resulted in less eye disease without a higher death rate.”(5)

Nor is it just among the researchers involved in the study that one finds OHPR skeptics. Several bioethicists, including David Magnus and Art Caplan in NEJM(6), and Ruth Faden and Renee Boss in a blog post from the Berman Institute of Bioethics at Johns Hopkins(7), have written to praise SUPPORT and bury OHRP—or at least its letter to the study leaders.

In what is to my mind the most authoritative of these critiques, John Lantos posts in The Hastings Center blog that criticisms of the study by OHRP and the advocacy group Public Citizen were not merely “off-target” but “dangerous” as well(8). “Off-target,” because SUPPORT’s critics tacitly assume what was only known after the study’s completion—that lower levels of blood oxygen were a greater threat to children’s lives than higher levels. “Dangerous,” because the OHRP’s careless response will discourage research, in part by making parents reluctant to participate in research. Indeed, as Lantos sees it, OHRP’s position rests on discounting completed research—which, at the time of the study, provided no basis for thinking that any position within the 85-95% band was more risky than any other.

The article’s text does indicate that a possible correlation between higher death rates and lower oxygen levels seem to have been on the researcher’s minds in designing the study. The authors note that SUPPORT results “add to the concern” that “oxygen restriction may increase the rate of death among preterm infants”(9). It’s natural to read this as suggesting that the SUPPORT study was in part motivated by pre-existing worries about greater risks of mortality at lower levels of oxygen support. Lantos’s post makes a distinction that might explain this apparent discrepancy. Determining whether a lower range was or was not safer in terms of mortality and morbidity was among the goals of the research; Lantos allows that the consent document for SUPPORT did not mention the study’s goals, and that they ought to have done so. But goals are different from risks—which were not, as he sees it, misreported. That would have been grounds for serious complain; the failure to state the goals he sees as a comparative peccadillo. For Lantos, it is OHRP whose behavior has been shocking, elevating the ongoing risk to babies inherent in neonatal practice by reducing the chances that further prospective randomized trials will help clinicians get a better grasp on what risks and benefits such children actually face.

Lantos, along with other OHRP critics, make such an effective case that one might wonder whether there was any moral (as opposed to legal or regulatory) reason for requiring consent at all. All babies enrolled in the study were treated according to the contemporary standard of care: no one had any reason to believe that any child’s assignment to either arm of the trial would have any impact on any outcome. No child therefore, was at added risk of harm. Nor was any child used as a “means to an end solely” since they were getting precisely the kind of treatment that, on the basis of medical knowledge, was most likely to help them. Further, apart perhaps from a decision that any treatment would not be in their child’s interest, it’s at least questionable whether parents have authority to prevent their children from getting oxygen support considered simply as a therapy: parents’ discretion with their children is wide ranging, but it doesn’t extend to exposing them gratuitously to grave risks. If therapy in such cases is close to mandatory anyway, and the research introduces no extra risks and is consistent with the respect due the children, why make any fuss about consent at all?

I’ll introduce another distinction by way of hazarding a reply. A parent’s decision to allow their child to be randomized to a position within the standard range doesn’t heighten their risks relative to what we know. Yet what a parent decides may well change what actually happens to her child. A given child could die if randomized to the lower range of support who might have lived if her physician had decided, based on clinical judgment or intuition or coin-flipping, to treat her at the higher range.

As it happened, this wasn’t likely—among the many useful things to be learned from Lantos is that study participants had better overall outcomes than children eligible for the study but not enrolled. Yet if my child had been one of those who were randomized to the low oxygen group and had died, I would have to live with the fact that my decision might have been one of the causal factors in my child’s death. I don’t think there’s anything idiosyncratic about such a reaction, and what it suggests is that arguably, moral responsibility, and certainly grief and guiltiness, track what we actually bring about, not only how rational we are in our choices. From that perspective, I should have wanted to know that the study was designed to answer an open question—were different positions within the customary range more or less dangerous for these tiny infants—and that my decision about participation was not routine, but could be of the highest consequence for my child.

The OHRP critics are very concerned not to discourage parents from participating in high quality research that targets pressing problem—that is, research like SUPPORT. They are right to be so. But to achieve that goal responsibly, we need to be alert to what matters to actual people, and not just to idealistic epistemic agents.

References:

  1. Tavernise S. Study of Babies Did Not Disclose Risks, U.S. Finds. New York Times website. http://www.nytimes.com/2013/04/11/health/parents-of-preemies-werent-told-of-risks-in-study.html?pagewanted=all&_r=0. April 10, 2013. Accessed May 3, 2013.
  2. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Early CPAP versus Surfactant in Extremely Preterm Infants. NEJM. 2010; 362(21): 1970-1979.
  3. NYT Editorial Board. An Ethical Breakdown. New York Times website. http://www.nytimes.com/2013/04/16/opinion/an-ethical-breakdown-in-medical-research.html. April 15, 2013. Accessed May 3, 2013.
  4. Macklin R. Informed Consent in Infant Research: Ethical Problems Remain. Albert Einstein College of Medicine Blog. http://blogs.einstein.yu.edu/?p=4403. April 18, 2013. Accessed May 3, 2013.
  5. Carlo WA, Bell EF, Walsh MC, for the SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Oxygen Saturation Targets in Extremely Preterm Infants. NEJM. April 17, 2013; DOI: 10.1056/NEJMc1304827.
  6. Magnus D, Caplan AL. Risk, Consent, and SUPPORT. NEJM. April 18, 2013; DOI: 10.1056/NEJMp1305086.
  7. Boss R, Faden R. Sensationalizing SUPPORT Harms Us All. Johns Hopkins Berman Institute of Bioethics Blog. http://bioethicsbulletin.org/archive/sensationalizing-support-harms-us-all/. April 25, 2013. Accessed May 3, 2013.
  8. Lantos JD. OHRP and Public Citizen Are Wrong about Neonatal Research on Oxygen Therapy. Bioethics Forum, a blog of the Hastings Center. http://www.thehastingscenter.org/Bioethicsforum/Post.aspx?id=6306&blogid=140. April 18, 2013. Accessed May 3, 2013.
  9. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Target Ranges of Oxygen Saturation in Extremely Preterm Infants. NEJM. 2010; 362(21): 1959-1969.

jim-nelsonJames L Nelson, PhD, is a Professor of Philosophy and the Associate Dean for Graduate Studies in the College of Arts and Letters 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 Friday, May 17. 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.