Tag: medical research

Bioethics for Breakfast: Aducanumab, Alzheimer’s: Having That Conversation

Bioethics for Breakfast Seminars in Medicine, Law and Society

Leonard M. Fleck, PhD, and Irving E. Vega, PhD, presented at the March 24 Bioethics for Breakfast session, offering perspectives and insight on the topic “Aducanumab, Alzheimer’s: Having That Conversation.” Bioethics for Breakfast is generously sponsored by Hall, Render, Killian, Heath & Lyman. This session was the second of a two-part series on the theme “Paradoxes of Aging: Living Longer and Feeling Worse.” The presentation portion of the session was recorded and is available to watch on our website.

Aducanumab, a drug designed to treat Alzheimer’s disease, has been the focus of intense medical, scientific, social, and ethical controversy. The FDA Advisory Commission voted almost unanimously not to approve the drug. The research trials failed to show that aducanumab offered significant clinical benefit to patients in the early stages of Alzheimer’s, and notably the enrollment of Black and Latino patients was disproportionately low. It came as a surprise that the FDA itself ultimately gave its approval to the drug, which costs $28,000 per year and is administered monthly through infusion in a hospital setting.

Fleck provided background on Aducanumab and the clinical trials carried out by the developer, Biogen, that led them to seek FDA approval. He defined the different stages of Alzheimer’s disease, noting that over six million Americans currently have been diagnosed with some degree of Alzheimer’s. Fleck also outlined the FDA’s approval process, including their vote to grant emergency use authorization with the expectation of phase four clinical trials completed within nine years. He also pointed out that Aducanumab’s effects are limited to mild cognitive impairment and mild Alzheimer’s, with no benefit in more advanced stages. However, there have been no other Alzheimer’s disease drugs in the past twenty years with promise of significant benefit.

Bringing up concerns of social justice, Fleck discussed the cost Aducanumab within U.S. health spending, particularly within the Medicare program. It is estimated that 85% of the estimated 3.1 million Americans with a mild Alzheimer’s diagnosis are Medicare eligible, meaning the annual cost to Medicare would be in the hundreds of billions of dollars for the drug and its associated costs. Fleck asked attendees to consider whether this spending would be a just use of limited health care resources.

Vega offered attendees questions to consider: is there sufficient evidence about the safety of the drug? Is there sufficient evidence about the effectiveness of the drug? Does the treatment address health disparities in Alzheimer’s disease? He discussed the biology of Alzheimer’s disease, outlining its effect on the brain, and pointing out what is still unknown about the disease. After defining scientific rigor, Vega walked attendees through concerns about the Aducanumab clinical trials, such as participant age and the inadequate representation of Black, Hispanic, American Indian or Alaska Native, and Native Hawaiian or Pacific Islander populations.

Focusing on these disparities, Vega shared facts pertaining to Black Americans being twice as likely to have Alzheimer’s compared to non-Latino white Americans, and Latino Americans being 1.5 times as likely, compared to non-Latino white Americans. Disparities exist with increased likelihood of comorbidities like stroke, heart disease, obesity, and diabetes. Given these facts, Vega shared concern for observed adverse side effects of Aducanumab, particularly brain swelling, microbleeds, and slow brain bleeding.

Questions from attendees generation discussion about advocacy work, insurance companies, and direct and indirect costs of Alzheimer’s disease. Fleck and Vega noted the cost of care for an individual with Alzheimer’s, in a long term care facility, is typically in the $80,000-$100,000 range per year. Indirect costs include the lost wages of caregivers, and stress experienced by loved ones. Vega also importantly pointed out the context of the approval of Aducanumab: a global pandemic, COVID-19 vaccine development, and the subsequent spread of misinformation. Attendees also participated in polling questions with hypothetical situations, asking whether they agreed or disagreed with the scenarios. Responses were varied, highlighting the complexities of the topic.

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About the speakers

Leonard M. Fleck, PhD, is a professor in the Center for Bioethics and Social Justice and the Department of Philosophy at Michigan State University. Fleck’s interests focus on medical ethics, health care policy, priority-setting and rationing, and reproductive decision-making. He explores the role of community dialogue (rational democratic deliberation) in addressing controversial issues of ethics and public policy related to emerging genetic technologies. More recently, he has been working on a book-length manuscript that addresses a number of ethical and policy issues related to precision medicine, primarily in a cancer treatment context.

Irving E. Vega, PhD, obtained his undergraduate degree in Biology from the University of Puerto Rico-Mayaguez Campus. He continued his research training in the Department of Cell Biology and Neuroscience at the Graduate School of New Brunswick, Rutgers University, earning his PhD. Vega completed a postdoctoral fellowship in the Neuroscience Department at Mayo Clinic Jacksonville, where he developed his research career focusing on the pathobiology of Alzheimer’s disease. Vega joined the faculty as an associate professor in the Department of Translational Neuroscience at the Michigan State University College of Human Medicine campus in Grand Rapids, MI in 2014. His research focuses on molecular and biochemical mechanisms that modulate the accumulation of pathological tau proteins in Alzheimer’s disease and related dementias. Vega is also working on ethnic disparities and the influence of ethnoracial factors on blood biomarkers in Alzheimer’s disease.

CRISPR Dangers Highlight the Need for Continued Research on Human Gene Editing

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

By Jennifer Carter-Johnson, PhD, JD

The excitement and potential of CRISPR to treat severe genetic conditions by editing disease-causing DNA has taken an unexpected hit. A recent Wall Street Journal article highlighted the unexpected results from a CRISPR study in which attempts to edit a human gene responsible for blindness resulted in the loss of the entire chromosome from the cells in the embryos. These results echo another study conducted in human cell lines published earlier in 2019.

CRISPR is a targeted gene editing process that allows scientists to direct genetic modifications with far more precision than prior procedures. CRISPR has been touted as a gigantic leap in the ability to modify DNA by creating or repairing pinpoint DNA mutations without affecting other areas of the chromosome on which the gene resides. The recent study indicates that the technique might not be as straightforward in humans – and thus neither will be its use to fight disease.

Blue DNA double helix puzzle with missing pieces
Image description: A partially assembled puzzle that is an image of blue double helix DNA molecule structures. Image source: Arek Socha/Pixabay

CRISPR Technology – Promise and Problems

The value in CRISPR mediated genetic modification can be seen in a wide variety of biotechnology products, such as genetically modified crops and new biologics. But perhaps the most exciting and most controversial potential for CRISPR can be found in the desire to modify embryonic genomes to remove genetic abnormalities for which we currently have no cure.

This promise of embryonic gene editing is appealing not only because it would remove the condition from the child born from the gene-edited embryo, but also because the offspring of that child would also be free of the condition. CRISPR gene editing – because it is done at the embryonic stage – creates germline mutations that are passed to future generations. In a therapeutic use of CRISPR, those mutations would be cures for often untreatable diseases.

However, it is this very promise that raises many of the problems with CRISPR embryonic gene editing. Much debate has surrounded embryonic gene editing. Until this recent news, there were fears that CRISPR may make gene editing too easy. The technological development of CRISPR in embryonic gene editing is moving at a breakneck pace as scientists around the world are working on procedures. Biohackers work in their garages and livestream the use of CRISPR to edit their own genomes.

Many are debating which genes should be targeted and how fast the research into actual trials should proceed. Most agree that severe diseases would be the best place to start, but should the technology be deployed for cosmetic benefits such as eye color, or diseases for which a treatment exists? The dangers of CRISPR editing are unclear, and there has been an informal moratorium on the use of the technology to create children. Despite that, there has been at least one rogue scientist who has created genetically modified embryos and brought them to full term birth.

International Policy on Human Gene Editing

The scientific research is not occurring in a vacuum. Each country decides how CRISPR can be used in its medical system – both when the technique is safe enough and on which diseases it should be used.

An international commission recently pronounced that the technology is not ready for clinic implementation because scientists don’t understand the full safety issues surrounding its use in human embryos. The commission described some of the potential clinical uses in the future and outlined a basic safety protocol for approval.

One of the creators of CRISPR, Jennifer Doudna, has also spoken out against applying CRISPR too hastily to embryonic gene editing. 

Based on the recent studies showing loss of chromosomes, the international commission and other scientists are correct to call for a moratorium on clinical embryonic gene editing.

Blue and green DNA double helixes and binary code
Image description: An abstract image of blue and green double helix structures and binary code (zeros and ones) against a black background. Image source: Gerd Altmann/Pixabay

CRISPR – The Path Forward

The setback in CRISPR gene editing does not mean that the technology and research should be discarded. The potential to change lives is too great; however, the dangers of use with our current understanding are even greater. So how do we move forward with CRISPR in embryonic gene editing? The answer must include balance – in research strategies and in voices.

While the technology is not ready for clinical use, and we have not yet determined which uses would be appropriate if it were available, the science should not stand still. The research surrounding CRISPR gene editing will yield insights into human biology that we cannot predict. For example, the loss of chromosome length in human embryonic cells undergoing CRISPR treatment seems to be different than the response of other species of embryonic cells. And debates about the appropriate use of the technology will allow us to discover more about ourselves as humans. 

As we debate the best way to develop and deploy CRISPR technology, we should look to a variety of stakeholders. Scientists have a solid track record in understanding when recombinant DNA technology has potentially hazardous implications. In the 1970s, the Asilomar Conference allowed scientists to put together research guidelines that allowed the technology to be developed without harming public health. In fact, the international scientific consensus not to use the technology such as described above indicates that scientists are beginning that work. Such a moratorium on clinical uses gives us time to understand how to deploy the technology in the safest manner.

Additionally, there is a role for the voices of the patients whose lives could be changed by the technology. Patients may not be in the best place to judge when the technology should be deemed safe enough to deploy, but they certainly will have input about which mutations cause hardships that merit the risk of germline editing. Many of these patients already work with scientists on potential treatments for their diseases. CRISPR discussions may open another avenue for many.

Finally, there is a role for legal regulation of the use of CRISPR. Governments should listen to the voices of scientists and potential patients in drafting these regulations. But as shown by the example of at least one rogue scientist, there needs to be teeth to the moratorium on CRISPR clinical use at this time. CRISPR and its use in human gene editing raise complicated issues and hold great promise as a powerful tool to defeat genetic diseases. The development of those technologies will not be straightforward or without risk and will require more basic science research to achieve clinical efficacy. But with proper planning, we may learn more about ourselves as humans on the path to a cure.

Jennifer Carter-Johnson photo

Jennifer Carter-Johnson, PhD, JD, is Associate Dean for Academic Affairs and Associate Professor of Law in the Michigan State University College of Law. Dr. Carter-Johnson is a member of the Michigan State Bar. She is registered to practice before the U.S. Patent and Trademark Office.

Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Tuesday, December 15, 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. Carter-Johnson: Biohacking: How a DIY Approach to Biology Can Shape Our Future; Web of Interests Surrounding Medicines Makes Patient Access Increasingly Difficult; Humanity in the Age of Genetic Modification; Defining The Spectrum of “Normal”: What is a Disease?; Dawn of False Hope: Spread of “Right To Try” Laws across the U.S.

Continue reading “CRISPR Dangers Highlight the Need for Continued Research on Human Gene Editing” →

We Should Tolerate and Regulate Clinical Use of Human Germline Editing

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

By Parker Crutchfield, PhD

In November of 2018, a Chinese scientist announced that he had edited the embryos of twin girls and that the twins had been born. The scientist, He Jiankui, used CRISPR, a revolutionary method of editing sequences of genes, to delete the gene CCR5 from the embryos’ sequences. The intention was to make the twins resistant to HIV. Editing human embryos and allowing those embryos to develop into living, breathing babies was widely condemned. However, now it appears possible, likely even, that the twins’ cognition was impacted, perhaps improved. This, however, was an off-target effect—it was unintended. On March 13, Nature published a comment from a group of scientists calling for a moratorium on clinical uses of human germline editing. This call is only for a moratorium on clinical uses, not on research on editing the human germline.

Despite the moratorium, I think a good argument can be made that tolerating the clinical use of human germline editing is morally permissible. Here is one such argument. The fact that He Jiankui edited the girls’ embryos suggests that it is inevitable that some scientists are going to engage in this behavior. Imposing a moratorium is unlikely to change this—the cat’s out of the bag. Given that the behavior is inevitable, we should ensure it is performed as safely as possible in order to reduce the risk of harm.

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Image description: an illustrated image of a strand of DNA with a piece being inserted, representing CRISPR-Cas9 technology. Image source: NIH Image Gallery/Flickr.

The Inevitability Argument

I’m claiming that because clinical use of human germline editing is now inevitable, we should tolerate and regulate it. Generally, arguments of this type don’t work. It isn’t generally true that just because something is going to happen anyway, we should not only tolerate that behavior, but also make sure that it is done safely. For example, it’s true that humans murdering other humans is inevitable (unless we can cognitively or morally enhance people through, for example, gene editing!). Despite prohibitions on murdering, it still happens and probably always will. But its inevitability doesn’t mean that we should tolerate it but ensure that it is done safely. We shouldn’t, obviously.

Sometimes the argument does work, though. Sometimes the inevitability of a behavior suggests that we should tolerate it under regulation. For example, people using IV drugs is, for the foreseeable future, inevitable. Given this inevitability, it is morally justifiable to tolerate the behavior and do what we can to ensure that it is done safely. One way we do this is through needle exchanges. More recently, similar arguments support the widespread availability of naloxone for overdoses. So, sometimes, but not generally, the inevitability of a behavior justifies the tolerance of the behavior in order to ensure it is performed safely.

Reducing Harm

Why does the Inevitability Argument work in the case of needle exchanges? Why does it fail in the case of murder? One difference is that we know murder is wrong. You can’t have the concept of murder without also having the concept of wrongness. To tolerate murder would be to tolerate something that is morally prohibited. But we should be more skeptical of the wrongness of IV drug use—it may not be wrong at all, to say nothing of policies that permit or prohibit it. Even if it is wrong, our confidence that it is so should be lower. Another difference is that in the case of needle exchanges with IV drug users, the tolerance and regulation is meant to reduce harm, not only to the users, but to society. On the face of it, it seems implausible that one could anticipate a parallel policy of tolerating and regulating murder to reduce harm. Rather, tolerating and regulating murder would increase harm.

Inevitability of Clinical Use of Human Germline Editing

Is the clinical use of human germline editing more like IV drug use, or more like murder? Supposing that whether the Inevitability Argument works depends on whether we know the behavior being tolerated is wrong, and whether tolerating it is intended to reduce harm, the clinical use of human germline editing seems much more similar to IV drug use than it does to murder. First, we don’t know whether the clinical use of human germline editing is wrong, unlike our knowledge that murder is wrong. Whether it is wrong or permissible or obligatory depends on a lot of factors, including on whether embryos have a moral status and whether we have a duty to future persons.

Second, what would tolerating the clinical use of human germline editing look like? It would require scientific and political oversight of methods, data, and follow-up clinical care. But more importantly, the tolerance and regulation of the clinical use of human germline editing would require that we know more about what the effects of it will be. The only way we can acquire this knowledge is by conducting research on the clinical consequences of editing the human germline. This is all to say that the intention of tolerating the clinical use of human germline editing is to reduce as much as possible any potential harms, both to the person whose embryo was edited as well as to society.

Tolerating and Regulating Clinical Use of Human Germline Editing

By these criteria, the clinical use of human germline editing looks much more like needle exchanges for IV drug use. If so, then the Inevitability Argument may work, suggesting that we should tolerate and regulate its practice. But this tolerance and regulation impose further requirements: we must closely monitor the behavior and support research on the effects of editing the human germline.

Scientists assert (without sufficient foundation, I think) that the behavior is wrong. Do we really know that the clinical use of editing the human germline is wrong? If so, what general principle grounds this knowledge? What are the consequences of this general principle for other lines of scientific research? Is the clinical use of human germline editing really inevitable?

parker-crutchfield-cropParker Crutchfield, PhD, is Associate Professor in the Program in Medical Ethics, Humanities, and Law at the Western Michigan University Homer Stryker M.D. School of Medicine, where he teaches medical ethics and provides ethics consultation. His research interests in bioethics include the epistemology of bioethics and the ethics of enhancement, gene editing, and research.

Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Thursday, April 18, 2019. 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.

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What are the ethical implications of gene-editing human embryos?

No Easy Answers in Bioethics logoNo Easy Answers in Bioethics Episode 13

What are the ethical implications of gene-editing human embryos? Do we risk stifling scientific advancement by banning such medical research?

Guests Dr. Leonard Fleck, Acting Director and Professor in the Center for Ethics and Humanities in the Life Sciences, and Dr. Marleen Eijkholt of Leiden University Medical Center in the Netherlands discuss the pros and cons, stemming from the recent news out of China of gene-edited babies. They share thoughts on the ethical implications of using such technology to alter human embryos, both now and in the future.

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—clinical ethics, evidence-based medicine, health policy, medical education, neuroethics, shared decision-making, and more. Episodes are hosted by H-Net: Humanities and Social Sciences Online.

Bioethics for Breakfast: Biobanking Tissue: Trash or Treasure?

Bioethics for Breakfast Seminars in Medicine, Law and SocietyJennifer Carter-Johnson, PhD, JD, and Tom Tomlinson, PhD, presented at the Bioethics for Breakfast event on December 6, 2018, offering their perspectives and insight on the topic “Biobanking Tissue: Trash or Treasure?”

“Big data”—repositories of biological, medical and demographic information about large numbers of people—is a critical platform for discovery of the causes of disease and potential new avenues for its treatment.

This data must come from us, the general public. Data about you might end up in a biobank because you’ve generously agreed to provide it, perhaps by agreeing to join the National Institutes of Health’s All of Us project that aims to recruit a broad representative sample of one million Americans.

Or it might already have been provided for use in research without your knowledge or consent. Research using specimens and medical information collected during your clinical care, once de-identified, doesn’t count as research on a “human subject” under the Federal regulations. Thus, your consent is not required. This source probably provides the great majority of information used in big data research, and acquiring and distributing it has become a multimillion dollar business.

This practice raises a host of questions. Doesn’t my specimen and my medical information belong to me, rather than to the hospital or clinic that collects it? Or have I thrown it away like my trash sitting on the curb each week? Although many people may feel comfortable providing this information for research, others might not. So isn’t it a simple act of respect to ask first? Or are researchers simply the medical equivalent of college students dumpster diving for cheap furniture that has been thrown away? Additionally, if we ask, and too many people say “no,” won’t critical research be hampered, to the detriment of all of us?

Dr. Tomlinson asked attendees to consider this question: Should clinically-acquired specimens and other medical information be treated like the trash that you have no control of once it has left your curb?

Dr. Tomlinson referred to a national study that his research team conducted in 2014 regarding willingness to give blanket consent, focusing on the fact that people care about more than risk – they have concern about how their materials may be used, and they worry about how much they should trust the research establishment. Dr. Tomlinson’s overarching argument was that respect for persons, a fundamental bioethics principle, requires informed consent.

Dr. Carter-Johnson also offered a question: whose treasure is it? Biospecimens and related data can be donated by patients and the public, can be clinically collected de-identified materials, and they can be samples given to private companies like 23andMe or Ancestry.com. Dr. Carter-Johnson also discussed a new startup offering to sequence your genome for free, and highlighted the variety of health and fitness apps that we give our data too. “When something is free, you are the product,” she said. A show of hands revealed that a minority of the attendees had gotten their DNA sequenced.

Dr. Carter-Johnson offered a legal perspective on tissue and genetic data in relation to property and privacy rights. She explained that individuals do not own their own tissue, citing the cases Moore v. Regents of California and Greenberg v. Miami Children’s Hospital Research Institute. However, there have been exceptions, and there are legal ways to “sell” your body (think plasma, bone marrow, sperm, or clinical trials).

When discussing privacy, Dr. Carter-Johnson used 23andMe and Ancestry.com’s privacy policies as examples. These policies are contractual, they are updated frequently, and they are often ignored by the consumer. However, push from consumers as well as bioethicists have led to these policies being more available and accessible.

Audience discussion brought up the famous Henrietta Lacks case, the future of biobank donor policies, and newborn screening programs and biobanks.

Jennifer Carter-Johnson, PhD, JD
Jennifer Carter-Johnson is an Associate Professor of Law at the Michigan State University College of Law and holds both a JD and a PhD in Microbiology. Professor Carter-Johnson uses her interdisciplinary training to study the intersection of law and scientific research.

Tom Tomlinson, PhD
Tom Tomlinson was Director of the Center for Ethics and Humanities in the Life Sciences from 2000 to 2018, and is a Professor in the Department of Philosophy. He chairs the Ethics Committee at Sparrow Health System, and has published widely on the ethics of biobank-based research.

About Bioethics for Breakfast:
In 2010, Hall, Render, Killian, Heath & Lyman invited the Center for Ethics to partner on a bioethics seminar series. The Center for Ethics and Hall Render invite guests from the health professions, religious and community organizations, political circles, and the academy to engage in lively discussions of topics spanning the worlds of bioethics, health law, business, and policy. For each event, the Center selects from a wide range of controversial issues and provides two presenters either from our own faculty or invited guests, who offer distinctive, and sometimes clashing, perspectives. Those brief presentations are followed by a moderated open discussion.

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.

Of Mice and Men

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

By Hilde Lindemann, PhD

According to a paper just published in the Proceedings of the National Academy of Sciences, using mouse models to study inflammatory disease caused by sepsis, burns, or trauma in humans is completely pointless. As the use of mice for this kind of research has long been the established practice, this means that years of study and billions of dollars have been squandered with nothing at all to show for it. There are several ethical issues here. For one thing, have we as a nation gotten so cavalier about nonhuman life that we are willing to injure lab animals routinely without even checking to see whether there’s a scientific reason for doing it? Can doctors trust the findings of medical research, and can patients, in turn, trust that their doctors’ recommendations are based on good science?

The new study, whose somewhat unwieldy title is “Genomic Responses in Mouse Models Poorly Mimic Human Inflammatory Diseases,” took ten years to complete and involved thirty-nine researchers from across the United States(1). It didn’t start out as a mouse study, though. The initial idea was to examine the white blood cells of hundreds of human patients to see what genes they were using to combat the ill effects of sepsis, burns, and trauma. When the results were in, interesting patterns emerged that seemed to suggest it would be possible to predict who would survive and who would end up in intensive care with a strong likelihood of dying.

However, when the group tried to publish their findings, no journal would accept them. Among other reasons the referees gave was that the researchers hadn’t shown that the genetic response was the same in mice. As the study’s contributing author, Ronald W. Davis put it, “They were so used to doing mouse studies that they thought that was how you validate things. They’re so ingrained in trying to cure mice that they forget we are trying to cure humans.”

Even so, the group figured there would be some similarities between mice and humans, so they took the referees up on their criticism. Because there are no studies that systematically evaluate, on a molecular basis, how well mouse models mimic human inflammatory disease, the group compared their own findings with what is known about genomic responses to sepsis, burns, and trauma in mice. The result? “Although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts.”

The reason appears to be one that even a non-scientist might have predicted: mice aren’t—get ready for it—human. For one thing, mice can eat rotten food and other garbage, because their bodies tolerate bacteria far better than human bodies do. It takes a million times more bacteria in the bloodstream to kill a mouse than it does to kill a person.

This should have been an obvious tip-off to researchers that there was something wrong with their assumption about the similarities between the species, as the likeliest explanation for mice’s high tolerance of bacteria would be that their immune systems are particularly powerful. And if that were established to be the correct explanation, it in turn should have been the tip-off to researchers that mice models for combating inflammatory disease would be no good, because the immune system is obviously implicated in that process as well.

As it turns out, inflammatory disease in mice that is caused by burns involve different groups of genes from that caused by sepsis, and if the disease is caused by trauma, still another group of genes is implicated. In humans, on the other hand, the etiology of the disease doesn’t matter—similar genes are used regardless of the cause. As a consequence, a drug that works in mice by disabling a particular gene that happens not to be involved in humans, or that actively helps combat the inflammatory disease in humans, could aggravate the disease or even kill the patient.

The implications of all this go far beyond the treatment of inflammatory disease. According to Mitchell Fink, an expert on sepsis at UCLA, funding agencies have required investigators to propose experiments using the mouse model. Obviously, peer-reviewed science journals have assumed the validity of that model as well. It will take a massive change in thinking, however, before better procedures can be established that shift research away from mice and toward the routine use of human tissues.

That shift may not happen. Bioethicists and other interested parties have been complaining for years, for example, against journals’ well-entrenched policy of not publishing negative results, even though these results, if widely known, might keep patients from ingesting useless drugs. Private IRBs answerable only to the pharmaceutical companies that have a vested interest in the drug trials they oversee are likewise well entrenched and unlikely to be dismantled any time soon. Large-scale federal funding for research sometimes goes to ill-designed studies that simply collect data, with no clear hypotheses that would give the data meaning. And these are only three of the many problems that plague medical research.

All the same, the “Genomic Responses” paper gives us a reason for optimism. It was, after all, the peer review process that goaded these researchers into exploding a basic research assumption. Never mind that the reviewers themselves not only bought the mistaken assumption, but insisted on it. The point is that, in doing so, they played an important, albeit unwitting, role in showing that it was false.

This post was written in response to the article “Mice Fall Short as Test Subjects for Humans’ Deadly Ills,” published on the New York Times website on February 11, 2013.

Reference:
1. Seok J, Warren HS, Cuenca AG, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. PNAS 2013; published ahead of print February 11, 2013, doi:10.1073/pnas.1222878110.

hildelindemannHilde Lindemann, PhD, is a Professor of Philosophy and Associate in the Center for Ethics Humanities in the Life Sciences at Michigan State University.

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