Article In Brief
Alzheimer's disease researchers and bioethicists discuss the pros and cons of exposing asymptomatic but at-risk individuals to disease-modifying and potentially harmful therapies in clinical trials.
The Alzheimer's disease (AD) research community experienced another setback earlier this summer when Novartis/Amgen's beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitor, known as CNP520 or umibecestat, joined the list of terminated therapies after an assessment found evidence of worsening cognitive function in participants in two pivotal phase 2/phase 3 studies in the Alzheimer's Prevention Initiative Generation Program.
As safety questions continue to surface in clinical trials of BACE inhibitors and other disease-modifying treatments for AD prevention, some experts have expressed concern about the ethics of exposing asymptomatic but at-risk individuals to potentially harmful therapies.
In conversations with Neurology Today, Alzheimer's disease researchers and biomedical ethicists noted that although more studies are yielding disappointing results regarding the safety of using BACE inhibitors for AD, there are still many unknowns. Do the possible benefits of these trials continue to outweigh the risks?
“The evidence suggesting problematic safety profiles for BACE inhibitors is mounting. Yet, there are still more questions than answers about BACE inhibitors, especially in preclinical AD,” Joshua Grill, PhD, associate director of the Alzheimer's Disease Research Center and director of the Institute for Memory Impairments and Neurological Disorders at the University of California in Irvine, told Neurology Today. “Perhaps we owe it to [participants] to get answers to questions like ‘Is it a class effect?,’ ‘Is there a safe dose?,’ or ‘What if we lowered amyloid by 30-40 percent over extended time periods, instead of acutely by 70-80 percent?’”
Jonathan Kimmelman, PhD, director of the biomedical ethics unit at McGill University in Montreal, said that he dislikes the words “failed trial,” which are often used after a trial is terminated. The success or failure “depends on whether they bring greater clarity to that hypothesis. In AD, the clinical trials have been successful—mostly disconfirming their pharmacological hypotheses. It's the drug development programs that have failed.”
The language matters here not only because negative results provide vital information for drug development but also because patients need to know that their participation in these trials was just as valuable regardless of the outcome, he added.
These trials have allowed researchers to better explain to individuals the true risk of participation, said Michael Rubin, MD, associate professor of neurology and neurotherapeutics and neurological surgery at the University of Texas Southwestern Medical Center.
When it comes to AD, “the unfortunate reality is that the histopathology related to the underlying disease can be very advanced by the time the patient is symptomatic,” Dr. Rubin, who is also chair of the UT Southwestern ethics committee, said. “If we're going to develop interventions that prevent the development of the underlying biology, then you really have to intervene early, which requires identifying people not with disease but at risk of developing disease. So there is the question: Is it fair to expose risk to people that may eventually have the disease?”
Dr. Rubin believes that answer is yes—these trials are still ethically permissible so long as researchers continue to mitigate risk to the greatest extent possible. “The key to these studies is not to close up shop, but to bring into the fold the information we gain from them.”
The Risks and Benefits
There are several unique challenges in weighing the risks and benefits of disease-modifying trials in preclinical AD participants, Dr. Kimmelman said, especially since at enrollment these individuals are in basic good health and generally have a high quality of life.
“In comparison with patients who have advanced disease, preclinical patients have more to lose should untoward safety issues arise. Extra research visits and procedures like brain scans, accrued over the lengthy span of a preclinical AD study, may prove especially burdensome.
“Our own meta-analyses [which have been accepted for publication] suggest that patients receiving disease modifying therapies in trials have higher rates of safety events and no overall benefit (in terms of disease progression) compared with patients in placebo arms. This unfortunately means that, as a general rule, patients are somewhat medically disadvantaged when they receive novel treatments in AD trials. This doesn't mean such trials are unethical. It does, however, somewhat raise the stakes of having a good, balanced informed consent discussion. And if we level with patients as we should during informed consent, it may present a challenge for recruitment,” Dr. Kimmelman added.
Stephanie Cargill, PhD, associate professor of health care ethics and associate professor of public health at Albert Gnaegi Center for Health Care Ethics at St. Louis University, told Neurology Today: “The upper limits of individual risks allowable with healthy participants usually amounts to the potential harms being reversible and/or temporary, or that a healthy person can be brought back to baseline, so to speak.”
In this type of research scenario, however, Dr. Cargill said, when the consideration is not comparing perfect health versus the risks of research, but rather potential disease versus the risks of the research, there are other “interesting, and rather unexplored risk/benefit implications.”
One important consideration, she continued, is a conceptual one: “While they are not clinically manifesting symptoms, being pre-Alzheimer's—or expected to have Alzheimer's manifest in the future—surely has an impact on people's emotional state, quality of life, stress level, etc. In addition, they may very well have something to lose if research cannot discover effective treatments for AD in the near future. In other words, unlike [for] healthy participants, there are personal in addition to societal benefits entering into the calculation.”
Another question to factor into the equation, Dr. Rubin suggested, is this: Can the researcher argue that the screening technique and the predictive models for those who will develop the disease are reliable enough to justify the risk imposed on the research participants?
“This adds motivation for the researcher as well as those that fund research in neurocognitive disorders to support studies that are designed for earlier screening,” he said. “These questions highlight the need for earlier identification for those at risk with a growing certainty so we can have a higher tolerance of imposing risk on those particular participants.”
What About Informed Consent?
The discussion of ethics in these trials, particularly as more safety data begin to emerge, hinges on transparency and a thorough informed consent process, commentators agreed. “The more direct and matter-of-fact you are about it, the better,” said Dr. Rubin. “Ultimately, the individual should know that it is reasonable to choose to participate in the study after hearing the pros and cons, but also that it is reasonable to choose not to,” he said.
We need to address the “therapeutic misconception” where people think the only two options are benefitting from the therapy or experiencing no change, Dr. Rubin emphasized. “They need to understand that it may have deleterious effects. And that they may never have the disease to begin with.”
He also expressed some concern, though based on speculation, that those who already take nutritional supplements for cognition may assume clinical therapies used in trials would be similar, and therefore cause no harm. These potential misperceptions should also factor into conversations around consent.
Another ethical question, Dr. Cargill said, is: “Who should decide whether the risks are appropriate? The person who may be facing a future with Alzheimer's or the research or regulatory community? I would argue that as long as the risks are clear, and what happened to previous people in these studies is disclosed to future participants (which is usually required), then the choice should be up to them.”
Even if participants may never go on to develop AD, “in which case in retrospect any cognitive deficits, especially if permanent, would not have been worth the risk,” the knowledge that they may develop AD and the potential of the research to prevent or ameliorate this possibility may still be worth that risk to the participants themselves, Dr. Cargill said.
The people enrolling in these trials are “remarkable, motivated, altruistic, and committed,” Dr. Grill agreed, and they deserve to know exactly what the researchers know and don't know before they enroll, so they can decide if a specific trial is right for them.
“Take, for example, the A4 study (Anti-Amyloid treatment in Asymptomatic Alzheimer's disease). At our site, despite amendments that quadrupled the dose of treatment and extended the duration of the study by 50 percent, of the 29 participants enrolled, only one—who progressed to moderately severe dementia—has withdrawn consent.”
It is important, Dr. Kimmelman stated, that researchers be absolutely transparent with patients from the outset of recruitment, stating the enormity of the challenges in AD drug development.
“They should tell patients that many disease modifying therapies in AD have looked very promising in nonhuman animals and even in preliminary human studies, and have nevertheless failed in rigorous clinical trials. They should also explain that in the past, AD treatments tested in trials have not benefited patients. They have, however, sometimes harmed them.” After a trial concludes or is terminated, research teams should always reach out to participants (and their caregivers) and share the results of the trial, he said.
Most of all, said Dr. Grill, “we owe it to these remarkable participants to give them a voice in decisions about what trials to do and how to do them. Indeed, their collective willingness to participate is a key determinant of the ethics of our research (see for example, the 2015 Neurology study by Kim, Karlawish, and Berkman).
“We owe the people participating in preclinical AD trials a tremendous amount. They give up their time and tissue for investigators and they put themselves at risk—all in the name of scientific progress and hope to help find effective therapies for Alzheimer's disease,” Dr. Grill told Neurology Today.
Dr. Grill has served as an investigator on studies sponsored by Eli Lilly & Company, Biogen Idec, and the Alzheimer's Disease Cooperative Study. Drs. Kimmelman, Rubin, and Cargill report no conflicts of interest.