FDA Approval of New Alzheimer’s Drug May Harm More Than It Helps

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

By Jennifer Carter-Johnson, PhD, JD

On June 7, 2021, the United States Food and Drug Administration (FDA) approved a controversial new Alzheimer’s Disease drug—aducanumab—to be sold by Biogen under the name Aduhelm. Alzheimer’s disease is estimated to currently be affecting over 6 million Americans plus their families, who must watch the mental decline of their loved ones and provide increasing levels of care as the disease progresses.

Controversy

Unfortunately, the approval of Aduhelm has generated a large amount of controversy because the FDA approval came despite the rejection of the studies of the drug’s efficacy by the FDA advisory committee. The opposition to the FDA’s approval has been so heated that three of the eleven-person advisory committee have resigned.

Detailed discussions of the science behind Alzheimer’s disease and the Aduhelm clinical studies can be found elsewhere. In summary, as Alzheimer’s disease progresses, protein plaques—amyloid and tau—build up in the patients’ brain. The progression of these plaques correlated with decreased mental acuity in patients. Therefore, drug candidates that target these plaques have been of interest to scientists for many years.

While the clinical data associated with Aduhelm supported a decrease in brain plaques in early-stage Alzheimer’s patients, the data did not show that decreasing plaques by the drug resulted in slowed progression of Alzheimer’s disease. In addition, the data showed that some patients have brain swelling as a result of the drug. Using this data, the FDA approved Aduhelm for broad use for all Alzheimer’s patients.

FDA Approval Process

Generally, to gain approval to sell a new drug, a company will complete a series of clinical trials to determine if a drug candidate is safe and effective for a given disease. Safety and efficacy are balanced against each other and consideration is given to the severity of the disease to determine if approval will be granted. As an example, a highly effective drug that is also highly toxic would not be approved as a simple headache remedy but may be approved as a treatment against a fast-growing, inoperable form of brain tumor. Conversely, an ineffective drug should never be approved no matter how safe it is—such are the wares of snake-oil salesmen of the past.

The FDA also has an Accelerated Approval pathway to allow drugs for diseases that have few treatments to proceed to market more quickly. It is under this accelerated path that the FDA approved Aduhelm. The accelerated pathway allows companies to use biomarker changes rather than disease improvement to show efficacy in the drug approval process. The FDA used the decrease in amyloid plaques as the biomarker for approval of the new Alzheimer’s drug—despite the fact that the clinical trial studies were submitted to show efficacy against disease progression. Moreover, the advisory committee was not informed of potential accelerated approval. Only after the clinical trial data was found unacceptable by the advisory committee did the FDA switch to the accelerated approval pathway. Perhaps most importantly, other drug candidates have been abandoned after amyloid plaque removal did not halt progression of the disease, so biomarkers may not be effective ways to judge the halt of Alzheimer’s progression.

The accelerated approval is, in effect, a contingent approval. Biogen will be allowed to sell Aduhelm, but it must gather data as to whether the drug is actually effective. If clinical data does not eventually support reduced disease progression, then the FDA can rescind the approval, and Biogen will no longer be able to sell the drug. The FDA’s approval of the Aduhelm may be harmful in the long run for several reasons.

Medicine IV infusion — Image description: A close-up photo of an IV drip containing clear liquid. Image source: stux/Pixabay.

Trust in FDA

The move by the FDA to approve Aduhelm could lead to a decrease in trust in the agency. First, the controversial nature of its approval over the recommendations of the scientists who reviewed the data created a controversy that is playing out across the news media as people wonder why an ineffective drug has been approved.

In fairness, the accelerated approval process is contingent, but due to the way the accelerated approval was used scientists did not have the opportunity to weigh-in on the use of biomarkers in that approval. That way in which the accelerated approval process was tapped, only after the regular approval process seemed doomed to fail, may well erode trust that the FDA evenly applies its own rules. Additionally, it is very difficult to rescind these accelerated approvals, and if the drug approval is rescinded public perception will likely be highly negative. Finally, according to Biogen it may take up to nine years to gather the data to complete the required studies.

New Drug Development

Aduhelm is not the only drug candidate in its class in clinical trials for Alzheimer’s disease treatment. Other drug candidates that include patients who receive a placebo rather than the drug candidate are undergoing clinical trials. Since these studies tend to be double-blinded—neither the doctor nor the patient knows if the drug or the placebo has been administered—patients will likely drop out of these other studies in order to be assured of receiving some drug. Thus, Alzheimer’s drug development will be slowed, in favor of a drug that has no demonstrable efficacy. Additionally, these new drug manufacturers may also ask for similar approval, based on biomarkers that may not be indicative of clinical effectiveness.

False Hope

Patients and Alzheimer’s advocates pushed for approval of this drug. But a drug with contingent approval may give these patients and their families false hopes. We have seen in Right to Try legislation–legislation allowing patients to use un-approved drugs in the FDA approval pipeline–both a fundamental lack of understanding of the FDA approval process as well as the desperation of patients for whom there are no clear treatment options. I have argued before that Right to Try laws prey on the emotionally fragile. Here the FDA’s controversial accelerated approval may have the same result—patients clamoring for a drug that does not work.

In addition, the cost of the drug will be borne by insurance companies that may well decide not to cover the drug. While the drug is approved for all stages of Alzheimer’s, clinical studies were only aimed at early-stage disease. In effect, the FDA has shifted its responsibility as gatekeeper for effective drugs to insurance companies for whom profit is a driving force.

Drug Cost

The cost of Aduhelm in light of the lack of efficacy data presents its own problems. Biogen has indicated that the average yearly cost of Aduhelm will be $56,000, not including the cost of doctors, hospital or clinic visits, and supplies to receive the infusions, or the cost of brain scans to monitor for swelling and brain bleeds as side effects. This cost, like most drugs, will be passed on to consumers through direct payments, increased insurance premiums, and higher budget expenditures for Medicare and Medicaid. One study reported that if 500,000 people on Medicare are prescribed the drug, it would cost $29 billion per year with copays of over $11,000 per year.

Biogen defends its pricing of the drug. According to its own press release, Biogen “established the price of Aduhelm based on the overall value this treatment is expected to bring to patients, caregivers, and society.” This expected value seems high for a drug that may not work but admittedly reflects normal drug company calculations in a system where insurance covers most prescriptions and the uninsured either do without or rely on the generosity of the drug company.

Because FDA approval is contingent, the FDA can remove the drug from the market if the required data do not show efficacy. However, the money paid for the failed treatment regime will not be refunded. Patients are paying to take this risk.

In the end, the FDA’s approval of Aduhelm will impact the way the agency is perceived, and the way other companies approach the drug approval process. Neither of these changes will be for the better.

Jennifer Carter-Johnson, PhD, JD, is Associate Dean for Academic Affairs and Associate Professor of Law at the Michigan State University College of Law.

Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Monday, July 5, 2021. With your participation, we hope to create discussions rich with insights from diverse perspectives.

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“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 series

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, 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 Course; To Floss or Not to Floss? That’s not the question

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Article from Dr. Laura Cabrera in November ‘Bioethics’ issue

Laura Cabrera photo An article by Center Assistant Professor Dr. Laura Cabrera has been published in the November 2019 issue of Bioethics. The article, “A human rights approach to low data reporting in clinical trials of psychiatric deep brain stimulation,” advocates for “the importance of reporting clinical trial data of invasive procedures in highly vulnerable populations, such as psychiatric DBS trials.”

Abstract: The reporting of clinical trial data is necessary not only for doctors to determine treatment efficacy, but also to explore new questions without unnecessarily repeating trials, and to protect patients and the public from dangers when data are withheld. This issue is particularly salient in those trials involving invasive neurosurgical interventions, such as deep brain stimulation (DBS), for ‘treatment refractory’ psychiatric disorders. Using the federal database ClinicalTrials.gov, it was discovered that out of the completed or unknown‐status trials related to psychiatric DBS up to November 2018, only two had submitted results to ClinicalTrials.gov. These results suggest that, despite federal requirements to report clinical trial data, reporting on psychiatric DBS trials is problematically minimal. It is argued that a human rights approach to this problem establishes a legal and ethical foundation for the need to report clinical trial results in this area.

The full text is available online via Wiley Online Library (MSU Library or other institutional access may be required to view this article).

Do patients have a duty to participate in clinical trials?

The Choice to Become a Research Subject: A First-Person Perspective

Event Flyer

Patients with serious illnesses are often invited to participate in clinical trials. After being diagnosed with advanced cancer, I became one of those patients. I had to choose between two options: a treatment regimen my doctors had recommended, or a trial evaluating different treatments for my disease. As someone who had taught and written about research ethics, and a long-time member of an Institutional Review Board, I was in some ways better prepared than many patients are to make this choice. And I knew about the important health benefits that come from research, as well as the arguments that patients have a duty to participate in research. Nevertheless, I decided not to enroll in the trial. Was this a defensible choice, or did I have a responsibility to contribute to a study that could help future patients in my situation?

March 22 icon Join us for Rebecca Dresser’s lecture on Wednesday, March 22, 2017 from noon till 1 pm in person or online.

Since 1983, Rebecca Dresser has taught medical and law students about issues in end-of-life care, biomedical research, genetics, assisted reproduction, and related topics. She has been a member of the Washington University in St. Louis faculty since 1998. Her newest book, Silent Partners: Human Subjects and Research Ethics, calls for including experienced study subjects in research ethics deliberations. She is also the author of When Science Offers Salvation: Patient Advocacy and Research Ethics and editor of Malignant: Medical Ethicists Confront Cancer. From 2002-2009, she was a member of the President’s Council on Bioethics and from 2011-2015, she was a member of the National Institutes of Health Recombinant DNA Advisory Committee.

This lecture is co-sponsored by the Program in Medical Ethics, Humanities & Law at Western Michigan University Homer Stryker M.D. School of Medicine.

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!

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Thorny Questions After a French Clinical Trial Goes Wrong

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

By Hannah Giunta, MPH, PhD

The problem of balancing access to new drugs with the conduct of rigorous clinical trials is not new. Indeed, readers might be interested in checking out a previous Bioethics in the News column that dealt with the right to try novel therapies. But, despite all the coverage, answers are hard to find. The public want access to new therapies that are safe and effective; but, both patients and professionals remain relatively uninformed of how and why the current process operates as it does. While we may rebalance the benefits and burdens of drug development, we can never provide early and widespread access without risk.

During his campaign, President Trump repeatedly promised to eliminate red tape at the Federal Food and Drug Administration (FDA) and speed the approval process for potentially life-saving medications; although, just how he will attempt to accomplish these objectives remains unclear. But, many ethicists are alarmed that current regulations and requirements do not go far enough. Early phase trials are by their design risky propositions. A recent CNN article by Jen Christensen brings these concerns to the forefront. In the article, Christensen highlights the trepidations of several leading ethicists about the current clinical trial process, emphasizing the fact that clinical trial sponsors do not need to provide proof of efficacy in order to begin early phase trials even though the trials can have significant risks for participants. Christensen focuses on a 2016 French clinical trial where six healthy volunteers were gravely injured, and in one case even killed, during a phase 1 trial of a novel painkiller. Previous trials of similar compounds had shown the agents to be clinically ineffective, but the company was not required to show proof of possible clinical efficacy before launching the trial. Ethicists in Christensen’s article suggest that the solution is creating an independent advisory body within the FDA charged with evaluating preclinical evidence of efficacy. Is this a good idea? Possibly, if indeed there is sufficient scientific literature to review and that literature correlates to some degree with efficacy in humans. But, it will not change the necessary step of administering a drug to humans for the first time. No amount of animal testing can establish precisely what will happen in vivo. The very nature of experimentation necessitates a certain level of risk, and early access without risk is impossible.

doctor-holding-stethoscope — Image description: a person’s hands are shown holding a stethoscope. They are wearing a white doctor’s coat. Image source: Alex Proimos/Flickr Creative Commons

In the current system, the FDA focuses on the safety and toxicity of compounds in phase 1 trials before moving on to efficacy assessments in phase 2 and 3 trials. The thought seems to be that toxicity is the first bar to overcome, since efficacy matters little if subjects are harmed by the drug itself. The classic model for phase 1 trials is the dose escalation study where participants are randomly assigned to receive an ever increasing dose of an experimental agent until unacceptable toxicities develop. In the current case, 90 healthy volunteers were recruited for just such a trial. News of a problem was first publicized in January 2016 after one participant was declared brain dead and five others were hospitalized (Bichell, 2016). Medical findings at the time indicated that the previously healthy man who died suffered a massive stroke in his brainstem. Five other men who received an equally high dose of the experimental agent after the first man became symptomatic were also hospitalized. Four suffered headaches, altered consciousness, and short-term memory difficulties (Bichell, 2016).

The question of how the trial went wrong is an indictment and profound misunderstanding of the current system. The investigators gave extremely high levels of the drug in order to determine what dose would be toxic and at what dose the pain receptor in question would be 100% blocked by the agent (Bichell, 2016). In other words, they did it for rigorous scientific reasons in accordance with their approved protocol. The scientific purpose of a phase 1 trial is to establish the dosage level that is toxic. Agents in a phase 1 trial are not dosed as they would be in clinical practice. A second complaint leveled at investigators concerns the fact that similar agents tested in previous trials had failed to markedly reduce pain (Bichell, 2016). Again, these complaints belie a poor understanding of the drug development process. Small differences in chemical structure can make a large difference in pharmaceutical outcomes, and scientists never know when a compound will radically change medical practice. The nature of research means that many drugs will not be successful, but a few will be. A final complaint lodged against the trial investigators suggested that some neurotoxicity in animal studies should have forced scientists to re-evaluate their plan for a phase 1 trial. But, even the scientist lodging this complaint admits that these injuries have happened with other experimental agents (not this particular class of drugs), and those agents caused no problems in human subjects (Bichell, 2016). Of note, the sponsor has made changes regarding how they are notified of subject hospitalization due to concern that additional volunteers received a high dose after the first man was hospitalized.

So, how does what happened last year in France factor into current promises to speed access to new drugs? By scientific standards, the phase 1 trial in question did not fail. It established the outer limits of toxicity. The outcry over what happened in France highlights the differences between how scientists think and how most patients and health care professionals think. Most drugs in the development pipeline will never gain FDA approval. Scientists are concerned with insuring safety and efficacy through a rigorous scientific process that takes time. What is a promising drug today may be a complete flop tomorrow. Expanding access requires that we accept a different standard of evidence (i.e. retrospective clinical data, clinical dosing guidelines without scientifically established maximum doses, etc.). Accepting different standards may make a lot of sense, but it will not mean access without risk. Perhaps the most important step we should take is to test drugs in people who suffer from the disease in question and not healthy volunteers. At least then, the burdens will be borne by those who stand to benefit. Yet, any of these solutions will not change the fact that medical progress is not a straight line, and we are putting people at risk today for the sake of tomorrow.

Hannah Giunta photo Hannah Giunta is an eighth year DO-PhD student at Michigan State University. She received her MPH in May 2015 and her philosophy PhD in May 2016. She is currently completing her medical school clerkships and plans to graduate in May 2017.

Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Thursday, March 9, 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.

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Bioethics for Breakfast: Compassionate Use: What Is in a Name?

bioethics-for-breakfast Anas Al-Janadi, MD, and Jennifer Carter-Johnson, JD, PhD, presented at the Bioethics for Breakfast event on November 17, 2016, offering perspective and insight on the topic, “Compassionate Use: What Is in a Name?”

Jennifer Carter-Johnson notes that The United States has a history of dangerous unregulated “medicines” that led to today’s drug regulations. Indeed, no drug is completely safe, and drug effects must balance safety against efficacy to win market approval for patients. Today’s drug regulatory process, in which 90% of drug candidates fail during clinical trials, and the potential desperation of end-stage patients requires that compassionate use balance protecting the public, encouraging new drug development and respecting patient autonomy. But Dr. Al-Janadi believes that we should think of this issue as an “early/expanded access opportunity” rather than “compassionate use.” One of his concerns is that there are presently lengthy delays in drug approval when drugs have shown some promising efficacy, thereby depriving patients of their benefit.

How do you believe a balance ought to be struck? Should there be public policies that reflect this balance? Or should this be left to the judgment of clinicians and patients, or the pharmaceutical industry? Does the current “right to try” legislation in many states need to be amended? These and other questions were addressed by the speakers and guests, creating a respectful and thoughtful discussion.

b4b-group_web — Left to right: Len Fleck, Jennifer Carter-Johnson, Anas Al-Janadi, and Libby Bogdan-Lovis pose for a photo following the event. Photo courtesy of the Center for Ethics.

Anas Al-Janadi, MD
Anas Al-Janadi is Associate Professor and Section Chief of the Division of Hematology and Oncology in the Department of Medicine at the Michigan State University College of Human Medicine.

Jennifer Carter-Johnson, JD, PhD
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.

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.

How did an OB-GYN in Puerto Rico become a key architect of the first birth control pill?

Choosing to Test: Dr. A. P. Satterthwaite and the First Birth Control Pill Clinical Trials in Humacao, Puerto Rico

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How did Adaline Pendleton Satterthwaite, an obstetrician-gynecologist (OB-GYN) working at a Protestant mission hospital in Puerto Rico, become one of the key architects of the first birth control pill? In 1952, Satterthwaite left the continental United States and went to Puerto Rico to work as an OB-GYN at Ryder Memorial Hospital in Humacao. She continued her work there through the early 1960s, but in 1957 she took on an additional job as Director of Family Planning Clinic and Research in Contraceptive Methods. In this capacity, Satterthwaite oversaw clinical trials of G.D. Searle & Co.’s Enovid, the first Food and Drug Administration approved oral contraceptive. This talk will examine Satterthwaite’s personal and professional reasons for bringing the trials to Humacao, Puerto Rico and demonstrate her central, if understudied, role in the development of Enovid.

Join us for Kathryn Lankford’s lecture on Wednesday, October 19, 2016 from noon till 1 pm in person or online.

Kathryn Lankford is a doctoral student in the Department of History at Michigan State University. She is broadly interested in the histories of medicine and science, gender and sexuality, and empire in the United States and Latin America. Specifically, Kathryn’s current research examines clinical trials of contraceptives in Puerto Rico during the mid-twentieth century. Before entering the PhD program in history at MSU, she received a B.S. in Biology from the University of West Georgia.

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! Visit our archive of recorded lectures. To receive reminders before each webinar, please subscribe to our mailing list.

Announcing the Fall 2016 Bioethics Brownbag & Webinar Series

The Center for Ethics and Humanities in the Life Sciences at Michigan State University is proud to announce the 2016-2017 Bioethics Brownbag & Webinar Series, featuring a wide variety of topics from under the bioethics umbrella. The fall series will begin on September 28, 2016, and you can attend the lecture in person or watch live online. Information about the fall series is listed below, and you can visit our website for more details, including the full description and speaker bio for each event.

Fall 2016 Series Flyer

sept28-bbag Ethics and Children with Differences in Sex Development and Gender Nonconformity
When should society constrain clinicians from intervening in these contentious arenas?
Wednesday, September 28, 2016
Joel E. Frader, MD, MA, is a Professor of Pediatrics and Professor of Bioethics and Medical Humanities at Northwestern University, and Medical Director of Bridges Pediatric Palliative Care Program at Lurie Children’s Hospital of Chicago.

oct19-bbag Choosing to Test: Dr. A. P. Satterthwaite and the First Birth Control Pill Clinical Trials in Humacao, Puerto Rico
How did Adaline Pendleton Satterthwaite, an obstetrician-gynecologist (OB-GYN) working at a Protestant mission hospital in Puerto Rico, become one of the key architects of the first birth control pill?
Wednesday, October 19, 2016
Kathryn Lankford is a Doctoral Student in the Department of History at Michigan State University.

nov9-bbag Trust and the Learning Health System
What will it take to trust the health system with all that information?
Wednesday, November 9, 2016
Jodyn Platt, MPH, PhD, is an Assistant Professor in the Division of Learning and Knowledge Systems in the Department of Learning Health Sciences at the University of Michigan Medical School.

In person: These lectures will take place in C102 (Patenge Room) 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? Every lecture is recorded and posted for viewing in our archive. If you’d like to receive a reminder before each lecture, please subscribe to our mailing list.

Dawn of False Hope: Spread of “Right To Try” Laws across the U.S.

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

By Jennifer Carter-Johnson, PhD, JD

Right to Try Laws Generally

Picture a mother with breast cancer hoping to see her daughters get married. Weep with parents as their nine year old son dies in their arms. Rally behind the newlywed couple fighting to experience just one anniversary. These are the people targeted by Right To Try (RTT) laws recently sweeping more than twenty states across the nation.

Based on model legislation put forth by the Goldwater Institute, RTT laws seek to allow terminally ill patients who have exhausted all approved drug therapies to access drugs that have not been approved for sale by the Food and Drug Administration (FDA). Proponents argue that the RTT laws empower terminally ill patients to attempt to try to save their own lives by allowing those patients access to drug candidates that have passed at least Phase 1 of FDA clinical trials.

FDA Clinical Trials Regulation

handful of pills — Image description: a hand is shown holding at least one dozen multi-colored pills. Image source: Flickr user Victor.

To understand why these laws are so troubling, it is important to put them in the context of the FDA regulation process. No chemical substance is completely safe – even drinking too much water can kill you. Cancer drugs are on the other end of the safety spectrum from water. Cancer drugs generally work because they kill cancer cells at a faster rate than they kill normal cells. The job of the FDA is to evaluate new drug candidates and approve one for sale when the proposed benefits of a drug outweigh its harms.

In order to make that determination, the FDA requires numerous studies culminating in a series of clinical trials using human patients. These clinical trials are divided into three basic phases with increasing numbers of patients enrolled in each. In a Phase 1 clinical trial, as few as twenty healthy patients are enrolled for a few months to determine a relatively safe dosage of the drug for use during further trials. Approximately seventy percent of drug candidates graduate from Phase 1 to Phase 2. It is not until Phase 2 that drug candidates begin to be assessed for effectiveness and side effects on a few hundred patients. Only about one third of the Phase 2 drug candidates show enough balance between effectiveness and side effects to move into Phase 3. Phase 3 trials involve large scale patient enrollment over several years to assess the true benefits and harms of a drug candidate. Of the drug candidates that enter Phase 3, only about twenty five percent are approved for marketing.

The drug approval pipeline is designed to screen large numbers of drugs to find the few that will be helpful in a given disease context. Of one hundred potential drug candidates, seventy will likely enter Phase 2; twenty three will pass into Phase 3 and about six will be approved for sale.

Impact of Right to Try on Patients and Society

Because most drug candidates enter Phase 2, a proposed cancer drug that kills normal cells too fast or causes side effects that kill a patient more quickly than the cancer will likely progress through at least Phase 2 trials before being dropped from the pipeline. That drug candidate would be available for use under the RTT Laws. In fact, a patient is far more likely to receive a drug candidate that will either do nothing to help the condition and/or have significant adverse side effects beyond the symptoms caused by the disease. Thus, patients who ask for drug candidates that have merely completed a Phase 1 trial very likely are banking on a false hope and may even have their lifespan decreased or their quality of life diminished.

Image description: A hand wearing a white latex glove is shown pouring large black pills from an unmarked bottle. Image source: Flickr user Health Gauge.

Other problems plague the patients invoking RTT laws. RTT laws allow companies to charge for the drugs, and small scale batches of drugs created for clinical trials are often highly expensive. RTT laws do not require insurance to cover those expenses, and many explicitly allow drug companies to go after the patient’s estate to recover costs. Thus, RTT laws are likely to primarily benefit those with resources to pay many thousands of dollars out of pocket. The poor will have no more access to drugs than before the law, and those with savings, life insurance policies, or retirement accounts will be tempted to drain those accounts for a false hope – likely leaving loved ones bereft of any financial buffer that had originally been planned.

Additionally, if a patient using an experimental drug has adverse side effects, he will further deplete his savings paying for care. Most RTT laws exempt insurance companies from paying for medical problems that arise while on an experimental drug. Public hospitals who cannot turn away those without insurance coverage may lead to a drain on the taxpayer. Because these laws protect both the drug company and the prescribing doctor from liability, the monetary and physical costs of any severe side effects will be borne by the patient alone.

Finally, there is the danger of the birth of a new snake oil market. Before the FDA regulated drugs for safety and efficacy, salesmen took advantage of customers to sell all sorts of tonics. We see similar problems in the practically unregulated supplement market today. The RTT laws hold the potential to underlie a new industry of drug candidates that have gone through Phase 1 to gain a sheen of FDA credence but that hold little chance of final approval.

More Reasonable Approach?

The access to drug candidates that have completed no more than a Phase 1 clinical trial is the worst form of false hope that threatens to cost those most vulnerable everything. In a nod to autonomy and the power of hope, perhaps a more reasonable approach would be to allow patients the right to try drug candidates that have entered into Phase 3 clinical trials. While many of the problems with cost, insurance and liability would remain, perhaps the most toxic and least effective drug candidates may have been screened from the pool of drug candidates.

Jennifer Carter-Johnson, PhD, JD, is an Associate Professor of Law in the College of Law at Michigan State University. Dr. Carter-Johnson is a member of the Michigan State Bar and the Washington 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 Thursday, November 5, 2015. With your participation, we hope to create discussions rich with insights from diverse perspectives.

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SUPPORTING Research Ethics: The Odds and the Outcomes

This 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:

James 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.

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Controversy

FDA Approval Process

Trust in FDA

New Drug Development

False Hope

Drug Cost

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The Choice to Become a Research Subject: A First-Person Perspective

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Right to Try Laws Generally

FDA Clinical Trials Regulation

Impact of Right to Try on Patients and Society

More Reasonable Approach?

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