For Our Own Good: Navigating Enrollment of Patients with Alzheimer’s Disease in Clinical Trials

Introduction

We live in a time of innovation. People today are faced with more options and opportunities than ever before regarding their medical care. This scientific progress is of undeniable benefit to society, providing hope and options for treatments that people need. However, progress also raises significant ethical questions around who has access to its benefits and who must bear its burdens. In order to understand a disease and treatments for it, it is necessary to enroll participants affected by it in research and clinical trials. But what should be done when the target group lacks the decision-making capacity to consent to participation? This paper will attempt to answer this question, discussing the enrollment of patients with Alzheimer’s Disease (AD) in research studies and clinical trials for treatments for AD. It will detail approaches to determining decision-making capacity, analyze pathways for consent when capacity is impaired, explore the unique risks and uncertainties of clinical trials and research, and consider societal impact. After consideration of the ethical concepts of autonomy, paternalism, beneficence, non-maleficence, and the framework of utilitarianism, the paper will propose recommendations for guidelines to better reflect the wishes of patients with AD regarding consent and participation in clinical trials. 

Background on Alzheimer’s Disease and Clinical Trials

Alzheimer’s disease is a brain disorder that slowly destroys a person’s memory, thinking skills, and eventually, their ability to carry out simple daily tasks. AD is theorized to be caused by the buildup of proteins in the form of amyloid plaques and tau tangles within the brain. This leads previously healthy neurons to stop functioning, lose connections with other neurons, and die. Changes in the brain related to AD begin years before any symptoms show; this time period is referred to as preclinical Alzheimer’s (Alzheimer’s Association).

Once symptomatic, the progression of AD is classified into three stages. First, mild AD is characterized by mild memory loss and cognitive difficulties. People may wander and get lost, have trouble handling money, repeat questions, take longer with usual tasks, and experience personality changes. People are often diagnosed with AD at this stage. The second stage, moderate AD, is connected to damage in the areas of the brain that handle language, reasoning, conscious thought, and sensory processing. Memory loss and confusion worsen, and patients may struggle to recognize family and friends. People may also be unable to learn new things and carry out multi-step tasks. Severe Alzheimer’s disease occurs once amyloid plaques and tau tangles have spread throughout the brain. Patients with severe AD cannot communicate and rely entirely on others for their care as they near the end of life (National Institute on Aging).

Currently, AD is estimated to affect more than 6 million Americans aged 65 or older, and it is the country’s 7th leading cause of death. The impact of AD is not limited to those who have the disease. AD takes a significant toll on families, communities, and the healthcare system, making this a truly pressing and widespread issue. 

There has been significant recent progress in understanding how Alzheimer's disease works, yet scientists remain uncertain about what causes AD, and how to treat and prevent it. With the projected number of new AD cases expected to double in the next four decades from about 514,000 in 2020 to about 1 million in 2060 (Doctrow), the need for progress is becoming increasingly urgent and widespread. 

There are two main types of clinical research: observational studies and clinical trials. Observational studies monitor people in their normal settings and look for patterns or changes over time. Clinical trials involve testing medical, surgical, or behavioral interventions on people. Clinical trials are the main way in which researchers are able to determine whether a new form of treatment or prevention is effective and safe (National Institute on Aging). Both kinds of research are necessary to advance scientific knowledge, but the only way to discover causation is through a clinical trial, which isolates variables and studies the impact or effectiveness of a certain intervention on the target population.

Clinical trials of compounds intended to treat AD, therefore, necessitate the involvement of patients with various stages of AD in order to accurately determine the safety and efficacy of these interventions. Excluding these patients from research studies may lead to results that do not demonstrate the effect of the treatment on the target population, leading to inaccuracy and risk to future patients (Mitchell et al.). This paper will focus specifically on the ethical implications surrounding the enrollment of patients with diminished mental capacity in clinical trials. 

Medical Decision-Making for Individuals with Alzheimer’s Disease

Decision-Making Capacity

First, it is necessary to discuss the process by which a patient’s ability to consent to a medical treatment is determined. For a patient to make a decision about their medical care, they must possess medical decision-making capacity. The medical definition of decision-making capacity is the ability of a patient to understand the benefits and risks of, and the alternatives to, a proposed treatment or intervention (including no treatment). Medical decision-making capacity has four key elements: patients must be able to (1) demonstrate understanding of the benefits and risks of, and the alternatives to, a proposed treatment or intervention (including no treatment); (2) demonstrate appreciation of those benefits, risks, and alternatives; (3) show reasoning in making a decision; and (4) communicate their choice (Appelbaum).

Generally, a patient’s capacity is readily apparent, and physicians intuitively assess capacity at every medical visit. If a doctor deems their patient’s choices logical and their understanding complete, it is probable that they will conclude that a patient has capacity. However, this assessment may be questioned if there is a change in behavior. This may include dialogue not proceeding in a logical fashion, a patient agreeing or disagreeing with a treatment unexpectedly or without foundation, or a patient having risk factors indicating impaired decision-making. The process of determining whether a patient possesses decision-making capacity begins with ensuring that there are no barriers to communication between the physician and patient, next ruling out any reversible causes of incapacity, and finally considering a patient's values and culture that may influence their choices (Barstow).

The next step would be to conduct a directed clinical interview to assess whether a patient demonstrates the four elements of decision-making capacity. Finally, if the directed interview does not clearly demonstrate capacity or if additional information is needed, the next step would be to use a formal assessment tool, which is more standardized and strict (Barstow).

Complexity in Determining Capacity for Patients with Alzheimer’s Disease 

Decision-making capacity can change over time. This can be due to a change in medical condition, notably the development of a neurological condition like AD or dementia, a change in mood or mental state, or any relevant change that affects a person's ability to reason and understand complex information. Therefore, medical decision-making capacity needs to be assessed whenever there's a medical decision to be made. This is especially true in the case of patients with AD or dementia, as their mental state is changing over time, and it is important that assessments of their capacity remain timely and accurate. 

Because an evaluation of medical decision-making capacity focuses on a patient's ability to make a choice in a certain scenario, it is not a universal assessment of their mental capabilities.  Whether a patient is deemed to have medical decision-making capacity will depend on the significance and impact of the choice that they are being asked to make.

Complexity arises, however, when attempting to define what decisions a patient with a known cognitive impairment should be allowed to make. It is impossible to determine a universal guideline that would properly address the unique situations of every patient. Therefore, the most effective method of determining capacity should be decided on a case-by-case basis, taking into account a patient's circumstances and the capacity they are deemed to have. 

Proxy Decision Makers

The main way in which healthcare decisions are made for someone who cannot make them themselves is through a substitute decision maker, or healthcare proxy. A healthcare proxy can be chosen by the patient in advance or, in some cases, appointed by a court. They are often someone close to the patient, such as a spouse, family member, or friend. In an ideal world, a person’s proxy is familiar with their values and wishes. This way, the choices that they make for the patient closely reflect what that person would have chosen for themselves. Healthcare proxies may be more helpful than other sources of information about a patient’s past wishes, as they can receive and adapt to new information. This may allow them to be more accurate in reflecting a patient’s wishes. If this is the case, the patient's autonomy is maintained as the proxy uses their understanding of the patient's preferences when making choices about their care. 

However, reality is not always in alignment with the ideal. Proxies are not necessarily able to correctly discern the wishes of the patients they represent. One study showed that people guessed one out of three end-of-life decisions for their loved one incorrectly (National Institute on Aging). This high error rate shows that even if a person is close to a patient, they may still struggle to have an accurate understanding of the patient's wishes and make these important decisions. In these common situations where the proxy may not fully understand the patient's wishes, they may consciously or subconsciously turn to their own ideas of what they think would be best, or what they would want in a similar situation. A proxy making these choices guided by incorrect understanding or paternalistic attitudes fails to promote patient autonomy, as the patient's desires are not preserved in their care. 

Proxies may have conflicts of interest. It is common that a proxy is also a patient’s caretaker, dependent, or someone else close to them. For people in this situation, their decision-making process may be complicated by conscious or subconscious consideration of the impact the decision will have on themselves. In combination with a lack of knowledge of a patient's original wishes, the choices of anything but an ideal proxy have significant space to stray from what the patient would choose for themselves, further undermining any preservation of autonomy.  

Advanced Directives

Another way to memorialize an individual’s wishes is through the use of an advance directive. Advance directives are legal documents that patients can draft before losing capacity to provide instructions for medical care in the event that they are unable to convey their wishes themselves. Advance directives are legally recognized, but there is potential for deviation or misinterpretation in unclear situations. There are three kinds of advance directives relevant to this paper’s discussion. 

First, a treatment directive or  “living will” is a legal document that tells doctors how a patient wishes to be treated if they cannot make their own healthcare decisions. It may detail which common medical treatments a patient would want, which they would like to avoid, and under what circumstances their choices apply. Second, a Durable Power of Attorney for Healthcare is a legal document that names a patient's healthcare proxy. One can be written in addition to, or instead of, a living will. Lastly, Advance Research Directives are legal documents that detail a person's wishes for future participation in research. They may include descriptions of procedures they are willing or unwilling to undergo, the level of risk they are comfortable with, and other details and preferences they deem important. This paper will begin with a discussion of treatment directives and later explore the use of research directives. 

The use of advance directives to dictate the medical care of a person who has lost capacity raises questions about whether previously-documented wishes truly comport with present-day preferences, calling into question when and to what extent these directives should be upheld. 

Ronald Dworkin advocates for strict adherence to a patient’s advance directive. He does so by distinguishing between the types of interests in a person’s life. He defines experiential interests as the things we do because we enjoy the experience of doing them. He considers these less important than critical interests, which are the hopes and aims that bring meaning to our lives. These are the choices that people make to fulfill their conceptualized narrative of their lives or to act in alignment with their characters. In cases where people have made clear their wishes for their end of life or their care in an advance directive, he says that their wishes should be honored to respect their autonomy and fulfill their critical interests (Dworkin). To limit this control would be “an unacceptable form of moral paternalism” (Dworkin 231). 

In contrast, Rebecca Dresser argues that a looser interpretation of advance directives, taking into account a patient’s present identity and desires, is necessary. She asserts that the inevitable change to identity people experience after developing dementia, even over the course of a natural life, makes them a different person. Therefore, she argues that advanced directives may not accurately reflect the person and preferences that exist in the present. Because of this, she argues that people should not be bound to the preferences voiced when their lives and identities were far removed from their current reality and identity (Dresser 35). Additionally, she argues that people are often not clear on their wishes. In addition to potential ambiguity, people are likely not to have had a complete understanding of what the implications of a disease or treatment will be when they drafted their advance directives. Dresser argues that “we do not advance people’s autonomy by giving effect to choices that originate in insufficient or mistaken information” (Dresser 35). This speaks to the unavoidable uncertainty present when attempting to make a decision without having all the available details, and the difficulty of conceptualizing one's future self, how they will experience the world, and what they will want. Therefore, past choices are not necessarily fully informed ones, and may not accurately represent what someone wants in the present day.  In this view, binding someone to past wishes would not accomplish the goal of preserving their autonomy. 

Unfortunately, no method to identify the present wishes of a patient is as effective as consulting the patient directly in the moment. Written advanced directives may have an advantage over querying proxies in that the statement of wishes or preference comes directly from the patient. They reflect the wishes of that patient at a point in time, which, while potentially removed from their present preferences, was at least representative of them at some point. As Dresser argues, it is true that people change significantly over the course of their lives. Overarching values and principles may remain similar, but technology, pain tolerance, and notions of what does and doesn't constitute a good or dignified life often change over time.  The long-term reliability/durability of an advance directive may depend on many variables. Therefore, strict adherence without consideration of current circumstances could result in pushing an unwanted option onto a patient. While written advance directives purport to preserve wishes for future reference, they may hinder patient autonomy if there is no way to update them to reflect a change in preference or adapt them based on a change in circumstance, new understanding of a situation, or a different reality. Therefore, Dresser holds that it is important to balance past wishes with an understanding of present circumstances. 

Proxies are beneficial to this end in that their decisions can be made with consideration of the current situation and their current experience of a patient. When able to deviate from the instructions of an advanced directive, proxies may be better able to make informed decisions for the patient, as they have a larger amount of information to inform the choice at hand, such as details about the methods and outcomes of a certain treatment. This supports a more informed decision than the patient’s surmises about a theoretical future when they drafted their advance directive. On the other hand, when a proxy may not have a full or accurate understanding of a patient’s preferences about a certain treatment, and may have differences in their values and principles by virtue of being a different person, having an advance directive can help inform their decisions.  This allows for the patient's wishes to guide decisions, while still enabling consideration of present circumstances and experiences that may have changed the patient’s earlier views.  This combination approach -- advance-directive-as-guidance-document plus proxy -- allows for the most effective preservation of patient autonomy as it aims to preserve choice and long-term preferences, while mitigating the risk of forcing an option on a patient that they no longer desire due to a change in experience or priorities. 

Participation in Clinical Trials

Ethical Guidelines

Clinical trials and research have their own set of regulations and ethical guidelines in order to ensure the protection of human research subjects. The current set of guidelines, the Federal Policy for the Protection of Human Subjects, or the “Common Rule,” was originally published in 1991 (“45 CFR Part 46 -- Protection of Human Subjects”). It was influenced significantly by the Belmont Report, which was created in 1974 by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (“Read the Belmont Report”). Both of these codes suggest a few basic ethical principles in response to the main ethical considerations that should guide research with human subjects. 

The first guideline is that there should be a separation between clinical research and medical practice. However, the line between practice and research is often blurred.

Generally, “practice” refers to actions that are taken solely to enhance the health and well-being of an individual patient and that have a reasonable expectation of success.

“Research” is defined as an action that aims to test a hypothesis, draw a conclusion, and contribute to generalizable knowledge. Research and practice can be conducted together if the research is on the efficacy and safety of a certain therapy. If there is any element of research in an activity, the general rule is that it should undergo International Review Board (IRB) review for the protection of human subjects. (“Read the Belmont Report”) 

The four foundational bioethical principles are ingrained within these guidelines. To begin, respect for persons refers to the idea that each individual should be treated as an autonomous agent and that those who lack autonomy are entitled to protection. Respect for a person’s autonomy requires the freedom for them to make their own decisions, be provided the necessary information, and not be manipulated in their decision-making.

(“Read the Belmont Report”) However, not all people are able to make decisions for themselves, and therefore are considered a vulnerable population requiring protection. The protection needed may range from exclusion from certain activities to merely ensuring they take action freely and understand the consequences. The level of protection and respect for autonomy should depend upon the risk of harm and the likelihood of benefit. 

Beneficence in this context is understood as a responsibility to do no harm to the patient and to maximize possible benefits and minimize possible harms. Conflict may arise within this principle when considering society at large as a stakeholder, and whether future societal benefits justify present-day harm to an individual. (“Read the Belmont Report”) 

Justice in this context relates to how the burdens and benefits of research should be distributed. An injustice occurs when a benefit that a person or group is entitled to is denied, or when a burden is unduly imposed on a certain person or group. Justice says that equals ought to be treated equally, but there is complexity in defining who is equal and who is unequal, and why. There are five main formulations for determining how burdens and benefits should be distributed. The first is by equal share, the second by individual need, the third according to individual effort, the fourth according to societal contribution, and the last according to merit. (“Read the Belmont Report”) 

Applying the principles and standards leads to the following requirements when conducting clinical trials with human subjects: 

Informed Consent

The first requirement is informed consent. Informed consent means that a choice is made with all relevant information being given, and that the decision to participate in the trial is made without coercion or undue influence. Necessary information includes information about the risks and benefits of the trial and how it will be run.  The patient must have the ability to ask questions and withdraw from the research at any time. The patient’s comprehension of the information is also required. It is the responsibility of the person providing the information to determine that the information presented has been fully understood and to adapt its presentation if it has not. If a person is unable to reach a full understanding, that indicates a lack of decision-making capacity, and alternative decision-making pathways are necessary. 

Informed Consent within Advance Research Directives 

Informed consent is a necessity for participation in research involving human subjects. However, complexity arises when a patient receives basic or preliminary information about a study and gives consent before having detailed information about the research. 

This issue can arise with advance research directives (ARDs). These are a type of advance directive that express a person’s willingness to engage in future research. They have been suggested as a means by which to facilitate research on incapacitated subjects, by allowing them to provide “advanced consent.” The intent is to sustain patient autonomy by allowing them to make a present decision about future research involvement, instead of relying on a healthcare proxy who may not have an accurate understanding of their wishes or possess deep knowledge of the implications of research trials (Pierce). 

The first issue in achieving informed consent with ARDs lies in the specificity of the information provided. In order to give informed consent, a patient is supposed to receive thorough information on a specific study, including the aims, procedures, risks, benefits, and potential conflicts of interest. These specific details of a study are referred to as ‘token disclosure.’ In the case of ARDs, however, the more common type of disclosure is a general description of a study, and theoretical details, referred to as ‘type disclosure’. This means that the details of a study may not be solidified or exist at all at the ARD’s creation (Heinrichs). Consenting to a study based solely on type disclosure poses a risk to the fulfillment of the requirements of informed consent; by definition, type disclosure does not include all the relevant information about the study. Heinrich suggests changing the standard for informed consent from the patient's understanding of the details of a specific study to the quality of the patient’s engagement in the informed consent process as a communicative act. He suggests that ARDs should be based on a continual communicative process between a patient and doctor to establish individual attitudes and processes. He suggests that researchers should also be involved in the drafting of an ARD, talking with the patient about what a study may look like and providing an opportunity for patients to ask questions to ensure that as full an understanding as possible is gained. If this route were taken, he suggests, individual participants could decide how much information they receive, and a waiver of information associated with token disclosure should be respected (Heinrichs). 

Approaching informed consent for patients with AD as a more continual process and communicative act may be more effective and thorough than attempting to gain consent based on a patient's understanding at a specific moment. This approach would take into account the fact that patients' lucidity and understanding can change day to day, and what is true of their understanding on one day may not be true on another. Evaluating the patient over a period of time allows a doctor to gain a fuller image of the patient and their preferences about treatment and participation in a study. This approach also aligns closely with the bioethical principle of respect for autonomy as it gives the patient more opportunity for their preferences to be heard, understood, and acted upon. 

While consenting to a study without full details of its procedure, risks, and benefits could be deemed in conflict with the conventional requirement that the patient receive all necessary and relevant information, engaging in a communicative process over a period of time might actually lead to increased understanding and information, and more thorough consent.

Informed consent is contingent upon the patient’s understanding of the information they are receiving. Presenting information to a patient over multiple days and conversations gives the patient more time to process and understand it than receiving large amounts at once, thereby promoting a patient's autonomy by enabling them to be more effectively informed. This is particularly true for a patient with diminished mental capacity, as it gives them multiple routes and chances to understand information outside of traditional pathways and methods that may become ineffective as the disease progresses. Having multiple conversations also allows a doctor to be more familiar with the patient's preferences and more accurately carry out the patient's wishes, instead of acting based on a solely best interests approach or the preference of the patient’s healthcare proxy. Ultimately, adapting the method of gaining informed consent to fit the needs and experience of AD patients by making it a continual and communicative act promotes patient autonomy by providing patients with more accessible pathways for understanding relevant information and greater opportunities to make their preferences known to those who will act on them. 

Another obstacle to securing meaningful advanced consent is the difficulty of knowing one’s future and future self, and purporting to consent on their behalf. When making a decision for one’s future, it is important to not only understand the information related to the choice but also imagine how this choice may affect one when coping skills and understanding of the situation change due to disease progression. They must consider not only how participating in a trial will affect them physically or psychologically in the future, but also how they think they will react if they do not understand why they are undergoing an uncomfortable procedure or do not remember consenting to it. It is relatively difficult to imagine how one might experience the world in the future if their brain and level of awareness differed greatly from their current life. Therefore, it would be beneficial for people to be aided with this imaginative element when drafting directives for their future care. They could be presented with vignettes or have the opportunity to speak to a patient with dementia or their family to better conceptualize the situation. Considering not only the information but also how it would affect them when they are in a different state could allow people to make more informed decisions.  It also could enable them to better understand their future experience and identity to better emulate who they will become and what they would want in that situation (Dresser).

Assessment of Risks and Benefits

The second requirement is an assessment of risks and benefits. This requires researchers to determine the potential harms to an individual and the potential benefits to that person and society at large. For the researcher, it is a means to examine whether the study is properly designed. For the IRB, it is a way to determine whether the risks to an individual are ethically supportable. And for the subject, is it a way to decide if they wish to enroll. Risks and benefits can encompass impact on the individual subject, their family, and society at large. Federal regulations require that the harm to the individual be outweighed by the sum of their individual benefit and the benefit to society via the knowledge gained from the research.

Justice and Selection of Research Subjects

The principle of justice requires fair procedures and outcomes in the selection of subjects. It requires that potentially beneficial opportunities not be offered only to one group while potentially risky research is offered to other groups based on bias or preference. It also requires that distinctions be drawn between groups of people that should or should not participate in research based on the ability of those groups to bear burdens or the appropriateness of further burdening already-burdened populations. Injustice may still arise in research -- even if the individual subjects were selected and treated fairly -- due to patterns of social, racial, sexual, and cultural biases institutionalized in society. Even if a group of marginalized subjects, such as people of color, or those of lower socioeconomic status, are represented equitably and treated fairly in a trial, their access to care and the general scientific knowledge about that group can still be hindered by systemic disadvantages created and institutionalized over time. 

Withdrawal From Studies

In order to uphold respect for vulnerable populations, it is necessary that participants are not forced to continue in a study if they show signs of dissent. Dissent may take the form of a physical or vocal protest or another form. Even when a person does not possess decision-making capacity, their objection to a certain treatment can still be clear and must be respected. It would directly contradict the principles of respect of persons and protection of vulnerable populations, as well as basic empathy, to subject someone to discomfort or pain when they are expressing distress or a desire for relief. Just because a person may have agreed or expressed willingness to bear discomfort in the past, there is no way to be certain that they continue to feel that way.  It must be considered that a patient may be having uncomfortable experiences that they no longer remember agreeing to endure and that they cannot understand. These realities would only heighten feelings of fear and discomfort. Therefore, it is most ethical to err on the side of caution and withdraw a patient who is showing dissent in order to avoid exploitation and unjustified pain.

The responsibility to determine the potential dissent of a research subject falls in part to their proxy or surrogate decision maker, if they have one. The proxy has a responsibility to discern what the subject would have wanted and to consider what the subject needs at the moment. Knowing the subject wanted to enroll in a study may prompt a proxy to enroll the subject and thereby carry out their perceived critical interest of helping others or advancing knowledge. However, study enrollment may not accurately represent the individual’s wishes at the time of actual study participation. It is very possible that the burdens that the individual faces during a study as a subject are greater than they expected when they gave consent.  This may be especially true in the case of advance consent based on type disclosure; people are often unable to know the full details of a particular study. A person with capacity can more readily withdraw from a study if the burden of participation becomes too much. Because people with AD may lack the capacity and ability to do so, the responsibility falls to their proxy or surrogate decision-maker to recognize their dissent and remove them from the trial if appropriate. 

Researchers have an additional responsibility when conducting trials on vulnerable populations. They must construct a method of evaluating a patient's well-being throughout the trial and identify if they are displaying dissent to participation at any time. They are responsible for ensuring respect for persons and the protection of vulnerable populations. If they were to continue or prioritize research despite the explicit discomfort or protest of a patient, they would be failing to fulfill their responsibilities and exploiting the patient. Researchers must be particularly attentive to the patient's well-being and possible withdrawal when a patient does not have a proxy, as the researcher then holds full responsibility for ensuring that the patient is a willing participant and there is no exploitation or coercion occurring. 

Some may question the legitimacy and significance of an expression of dissent by a person with AD. They may note that patients are often uncooperative, even with necessary and routine activities. Temporary discomfort may be justified for actions deemed necessary for the patient’s care, as a lack of intervention may result in more pain or more significant illness. However, in the case of activities associated with participating in a clinical trial, enduring discomfort cannot be said to be “necessary” and the potential for personal benefit is not necessarily clear.  When not justified by a direct necessity or benefit to the individual patient, inflicting additional discomfort on a vulnerable individual showing dissent cannot be condoned. Allowing this practice could be a slippery slope towards the exploitation of vulnerable populations. Researchers are incentivized (financially, intellectually, and contractually) to keep patients in their studies in order to generate more data to form the basis for study results. If researchers were not obligated to respect dissent and withdraw dissenting patients, those incentives could result in exploitation and abuse of members of vulnerable populations. 

Some might seek to justify keeping dissenting patients with AD or other cognitive impairments in trials on the grounds that they will forget their discomfort.  However, this argument does not withstand scrutiny.  Using this logic, one could justify the mistreatment of any group under the idea that they will forget the experience later, which we will all do after death. Dismissing the pain of another person to use them as a means to one's own ends directly conflicts with the imperative to protect vulnerable populations and creates a slippery slope towards exploitation. 

Societal Impact of Clinical Trials

In this section, I will explore the individual and societal consequences of the current process of enrolling patients with AD in clinical trials and the potential outcomes if the requirements for participation were made less restrictive. 

Selection criteria determine who is eligible to participate in a clinical trial. When chosen well, they ensure the generalizability, efficacy, and safety of a study (Fogel). However, overly restrictive criteria may result in a study that does not accurately represent the target population, resulting in reduced generalizability and a disproportionate exclusion of historically underrepresented groups. One study found that age exclusions appeared in 87% of trials, making it the number one-ranked eligibility criterion identified. The majority of trials had criteria that may act as a barrier to achieving diverse and equitable recruitment into AD/ADRD clinical trials: 82% of trials had poorly operationalized criteria, meaning that criteria may be vague and lead to inconsistent interpretations and varying restrictions across studies; 88% had at least one criterion that may disproportionately exclude underrepresented populations, such as excluding a genetic predisposition that is more common in Black individuals; and almost 60% of trials did not plan to enroll non-English speaking participants. (Mitchell et al.)

It is essential to ensure that eligibility criteria are determined by balancing both scientific necessity and equitable trial design. Diverse and equitable representation is essential not only for the generalizability of studies but also to ensure that the historic underrepresentation of marginalized populations in medicine is not perpetuated further. 

Immediate consequences 

A primary motivation for a person to enroll in a clinical trial is the hope that the intervention being tested will work and be of utility to them. This potential for individual benefit, even if it is not guaranteed, has the potential to be overpowering, even in spite of risks, in a situation where a patient lacks other options and is therefore desperate. This desperation makes the process of gaining informed consent from both patients and proxies even more difficult. Desperation may further cloud the decision-making of a patient, as the potential for risks is overshadowed and possibly even ignored based on the hope for personal benefit. A sense of desperation may also undermine the objective judgment of a proxy, particularly if the patient is somebody close to them, or if they have personal and emotional stake in their treatment.  Despite emotions and hopes that may make objective judgements more difficult, it is important for the prospective subject to fully understand and process both the risks and benefits, particularly the idea that individual benefit is not guaranteed. This ensures that a patient does not enroll under false pretenses, which would fall into the realm of coercion. 

In contrast to the potential benefits of participation, there can also be unintended harm and discomfort to the individual. When a patient is living with AD, their consistent understanding of the current moment, what brought them there, and what is actually going on is not guaranteed. A physically uncomfortable experience would only serve to exacerbate these feelings of confusion and fear. Therefore, when conducting research on mentally impaired populations, it is necessary to place empathy at the forefront. 

Long-Term Consequences

The long-term goal of conducting research is to generate generalizable knowledge to serve the larger population. It is undeniable that the possibility of understanding, preventing, and treating AD would be of great utility to many people, especially with the predicted rise in cases in the upcoming years. Taking a utilitarian approach, therefore, one could argue that prioritizing the progress of research is the most ethical course of action as it could provide the greatest benefit to the greatest number of people, despite the potential exploitation or harm to a minority. This perspective could therefore support the loosening of guidelines around enrollment and standards for informed consent in order to reduce barriers to participation, and therefore, progress. 

However, loosening the requirements for informed consent runs the risk of promoting coercion and exploitation of a vulnerable population. Without strong standards for informed consent, people are not guaranteed adequate information about the study and their potential enrollment, and may be at greater risk for undue external influences on their decisions. By prioritizing the potential benefit for the many, appropriate focus on the needs and care of an individual may be lost, and people may be used as a means to an end. From a deontological perspective, this is never ethically permissible. Additionally, such exploitation directly contradicts the need to protect vulnerable populations. 

The needs for progress in society and the protection of vulnerable populations are in conflict in this situation, so the critical question is how to balance them.  It is unethical to alter guidelines to advance societal knowledge by aiming to increase patient enrollment or retention in a way that would result in the exploitation or coercion of vulnerable populations. This eliminates the possibility of greatly changing standards for informed consent, creating stricter requirements for study withdrawal, or diminishing respect for autonomy by giving proxies more latitude to disregard patients’ advance directives. 

However, there is room to improve and alter study enrollment criteria.  By expanding the number of people who are eligible to participate in a study, the pool of applicants and eventual enrollment should both increase. Because patients should be withdrawn at signs of dissent, larger study populations may be necessary. Many of these enrollment criteria are unjust themselves as they limit the diversity and generalizability of studies arbitrarily. Ensuring that exclusion criteria are limited to those necessary for a study expands eligibility, diversity, and generalizability, which are all essential to making progress in research. This change can be made without sacrificing the protection of vulnerable populations. 

Conclusion

It is necessary to maintain strong guidelines around informed consent, where patients are provided with all relevant information before making their decision. Ongoing conversations with a healthcare professional can improve understanding of future medical treatment or research. Despite the complexity that arises with gaining this understanding, it is necessary to ensure an autonomous decision that is fully informed and free of coercion. 

Advance directives can help preserve patient autonomy and are an elegant option to accomplish this goal by serving as a way to improve a proxy’s understanding of a patient's fundamental values. They are not as effective at preserving autonomy if they are implemented in a way in which there is no room for deviation or interpretation to reflect the flexibility of identity and changing ideas. Therefore, advance directives are most effective and ethical when they serve as informational, but not binding, documents. 

The involvement of a proxy or surrogate decision maker may allow a patient's wishes to be preserved in a more dynamic manner that appreciates shifting preferences. It is essential, however, that the proxy is informed about a patient's wishes and will attempt to honor them in good faith. This way, they can act as an extension of the patient and their autonomy, instead of furthering their own desires due to misinformation or paternalistic attitudes. 

A patient should be withdrawn from a trial in the event of uncharacteristic distress, as it serves as a demonstration of dissent to participation. Responding to signs of dissent is necessary to respect patient autonomy and protect vulnerable populations against exploitation. 

Advancing societal knowledge of AD and the protection of individuals involved in that research are both of utmost importance. However, it is not ethical to prioritize one to the extent that it would exploit the other. Therefore, guidelines around informed consent, withdrawal, and pathways to preserve patient autonomy must be preserved. There is, however, room for improvement in the area of exclusion criteria. Ensuring that exclusion criteria consist only of restrictions that are necessary for the running of a study would increase eligibility, diversity, and generalizability. This would effectively advance societal knowledge without sacrificing the protection of vulnerable populations. 

Works Cited

“Advance Care Planning: Advance Directives for Health Care.” National Institute on Aging, 31 Oct. 2022, www.nia.nih.gov/health/advance-care-planning/advance-care-planning-advance-directives-health-care.

“Alzheimer's Disease Fact Sheet | National Institute on Aging.” National Institute on Aging, 5 April 2023, https://nia.nih.gov/health/alzheimers-and-dementia/alzheimers-disease-fact-sheet. Accessed 14 February 2025.

“Alzheimer’s Stages - Early, Middle, Late Dementia Symptoms | alz.org.” Alzheimer’s Association, www.alz.org/alzheimers-dementia/stages#overview.

American Bar Association Commission on Law and Aging, et al. Assessment of Older Adults With Diminished Capacity: A Handbook for Psychologists. book, 2008, www.apa.org/pi/aging/programs/assessment/capacity-psychologist-handbook.pdf. 

Appelbaum, Paul S. “Assessment of Patients’ Competence to Consent to Treatment.” New England Journal of Medicine, vol. 357, no. 18, Oct. 2007, pp. 1834–40. https://doi.org/10.1056/nejmcp074045.

“The Belmont Report.” HHS.gov, 26 August 2024, https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/index.html. Accessed 15 February 2025.

Doctrow, Brian. “Risk and future burden of dementia in the United States.” National Institute on Aging, 11 March 2025, https://www.nia.nih.gov/news/risk-and-future-burden-dementia-united-states. Accessed 2 April 2025.

Dresser, Rebecca. “Advanced Directives in Dementia Research.” IRB: Ethics & Human Research, vol. 23, no. 1 January-February, 2001, pp. 1-6. JSTOR, https://www.jstor.org/stable/3563979?seq=1. Accessed 15 February 2025.

Dresser, Rebecca. “ADVANCE RESEARCH DIRECTIVES: IMPLEMENTATION ISSUES.” Journal of the American Geriatrics Society, vol. 48, no. 7, 2000, pp. 859-860, https://doi.org/10.1111/j.1532-5415.2000.tb04773.x. Accessed 17 February 2025.

Dresser, Rebecca. “Dworkin on Dementia: Elegant Theory, Questionable Policy.” Hastings Center Report, no. November-December, 1995, pp. 32-38. Accessed 15 February 2025.

Dworkin, Ronald. Life’s Dominion: An Argument About Abortion, Euthanasia, and Individual Freedom. Vintage, 1994.

“Federal Policy for the Protection of Human Subjects ('Common Rule.” HHS.gov, 27 March 2024, https://www.hhs.gov/ohrp/regulations-and-policy/regulations/common-rule/index.html. Accessed 15 February 2025.

Fogel, David B. “Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review.” Contemporary Clinical Trials Communication, vol. 11, no. September, 2018, pp. 156-164, https://www.sciencedirect.com/science/article/pii/S2451865418300693?via%3Dihub#sec4. Accessed 12 2 2025.

“45 CFR Part 46 -- Protection of Human Subjects.” eCFR, https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-A/part-46. Accessed 15 February 2025.

Heinrichs, Bert. “Advance research directives: avoiding double standards.” BMC medical ethics, vol. 22, 2021. BMC Medical Ethics, https://bmcmedethics.biomedcentral.com/articles/10.1186/s12910-021-00704-5#citeas. Accessed 15 February 2025.

Kim, Scott Y. H., et al. “Current State of Research on Decision-Making Competence of Cognitively Impaired Elderly Persons.” American Journal of Geriatric Psychiatry, vol. 10, no. 2, Mar. 2002, pp. 151–65. https://doi.org/10.1097/00019442-200203000-00006.

Kramarow, Ellen A. “National Health Statistics Reports, Number 203, June 13, 2024.” CDC, 13 June 2024, https://www.cdc.gov/nchs/data/nhsr/nhsr203.pdf. Accessed 23 February 2025.

Marson, Daniel C., et al. “Consistency of Physician Judgments of Capacity to Consent in Mild Alzheimer’s Disease.” Journal of the American Geriatrics Society, vol. 45, no. 4, Apr. 1997, pp. 453–57. https://doi.org/10.1111/j.1532-5415.1997.tb05170.x.

Mitchell, Alexandra K., et al. “Analysis of eligibility criteria in Alzheimer's and related dementias clinical trials.” PubMed, 1 July 2024, https://pubmed.ncbi.nlm.nih.gov/38951633/. Accessed 12 February 2025.

“More Women Get Alzheimer's Than Men. Why?” Alzheimer's Association, 10 September 2020, https://www.alz.org/news/2020/more-women-get-alzheimer-s-than-men-why. Accessed 23 February 2025.

Palmer, Barton W., and Alexandrea L. Harmell. “Assessment of Healthcare Decision-making Capacity.” Archives of Clinical Neuropsychology, vol. 31, no. 6, Aug. 2016, pp. 530–40. https://doi.org/10.1093/arclin/acw051.

Pierce, Robin. “A Changing Landscape for Advanced Directives in Dementia Research.” Social Science & Medicine, vol. 70, 2010, pp. 623-630. Science Direct, https://doi.org/10.1016/j.socscimed.2009.10.037. Accessed 16 February 2025.

“Read the Belmont Report.” HHS.gov, 15 January 2018, https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html. Accessed 15 February 2025.

Vellinga, A., et al. “Competence to Consent to Treatment of Geriatric Patients: Judgements of Physicians, Family Members and the Vignette Method.” International Journal of Geriatric Psychiatry, vol. 19, no. 7, June 2004, pp. 645–54. https://doi.org/10.1002/gps.1139.

Walker, Keenan. “Data shows racial disparities in Alzheimer's disease diagnosis between Black and white research study participants.” National Institute on Aging, 16 December 2021, https://www.nia.nih.gov/news/data-shows-racial-disparities-alzheimers-disease-diagnosis-between-black-and-white-research. Accessed 23 February 2025.

Wang et al, Rong-Ze. “Genetically determined low income modifies Alzheimer’s disease risk.” Annals of translational medicine, vol. 9, no. 15 (2021): 1222, 2021. PubMed, https://pmc.ncbi.nlm.nih.gov/articles/PMC8421944/. Accessed 23 February 2025.

“What Are Clinical Trials and Studies? | National Institute on Aging.” National Institute on Aging, 22 March 2023, https://www.nia.nih.gov/health/clinical-trials-and-studies/what-are-clinical-trials-and-studies. Accessed 14 February 2025.