Argumentative Essay: Ethical Concerns in the ADAPT Clinical Trial

This argumentative essay critically examines the ethical considerations of the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), a clinical drug trial evaluating the use of naproxen and celecoxib for Alzheimer's disease prevention. The essay explores the ethical implications of early trial termination due to cardiovascular risks associated with celecoxib, focusing on scientific validity, social value, informed consent, and independent review. It discusses how the premature halting of the trial potentially compromised the scientific integrity of the results, potentially misled clinicians, and raised concerns about patient safety and the balance between benefits and risks. The analysis highlights the importance of rigorous stopping rules, proper patient information, and the need for comprehensive data to ensure ethical conduct in clinical trials. The essay also considers the importance of participant characteristics, such as age and lifestyle, in assessing risks. The essay concludes by underscoring the importance of ethical considerations in clinical trials to safeguard participant well-being and the integrity of research findings.

Running head: ARGUMENTATIVE ESSAY
Ethics in Healthcare
Name of the Student:
Name of the University:
Author Note:

1ARGUMENTATIVE ESSAY
Introduction:
Clinical drug trials have become increasingly popular in the field of healthcare
research. Clinical trials serve as evidence to find best treatment option for patients.
Successful clinical trials serve as a licensure to deliver evidence based interventions
that are prescribed by healthcare practitioners who would otherwise make a clinical
judgement merely on the basis of their experience which could be biased and
misleading. On account of the importance of the clinical trial results it is vital to
ensure that trials are conducted ethically and the results obtained are scientifically
sound as well as maintain patient autonomy and safety (Deichmann, Kousel-Wood,
& Breault, 2016). One of the clinical drug trial studies The Alzheimer’s Disease Anti-
inflammatory Prevention Trial (ADAPT) conducted in 2006 intended to evaluate the
conventional NSAID naproxen sodium and the selective COX-2 inhibitor celecoxib
for the primary prevention of Alzheimer’s dementia (AD). However, another drug trial
Adenoma Prevention with Celecoxib (APC) was conducted in 2004 and this trial
reported increased cardiovascular risks accompanied with the use of celecoxib. On
the basis of the increased risk factors, the ADAPT Steering Committee suspended
the treatment intervention and enrolment of the subjects for conducting the clinical
trial.
Overview of the trial:
This trial was sponsored by the United States National Institute on Aging, and
the recruitment process initiated from the year 2001. The blue print of the experiment
suggested that 2625 participants would be recruited who would then be randomised
into three arms: naproxen, celecoxib and placebo. It was then assumed that the trial
would run for seven years. However, the experimental study came to an abrupt end

2ARGUMENTATIVE ESSAY
when the decision was undertaken by the NIH to terminate the study early. It should
be mentioned here that the decision undertaken was based on the part of results
from other studies that have showed an increased risk of certain medical adverse
events, such as myocardial infarction and stroke in patients taking celecoxib and
other types of COX-2 inhibitors. However, this data was not estimated at the time of
designing the trial. However, the ADAPT studies have further investigated the
chances of the medical adverse events (Martin, 2006).
The decision to stop a clinical trial early is undertaken mainly to minimize the
harm and maximize the benefits for the participants. Research studies suggest that
when the results show no justified cause for subjecting the participants to potential
risks by continuing the trial, the trial must be stopped (Streiner, 2019). However,
stopping the clinical trial early needs to be grounded by the ethical principles. In the
ADAPT trial, there were four ethical considerations that were applied when the NIH
decided to stop the trial early simply by just looking at the cardiovascular risks in
ADART.
Scientific Validity:
Firstly, the purpose of a clinical drug trial is to investigate whether the study
drug is safe and effective for patients and it must closely approximate the accurate
impact of the drug and should not be misleading. This requires the study procedure
to follow the scientific standard and to ensure the results confer to scientific validity
(Wears, 2015). Statistical theory and experiential evidence imply that early stopping
of a drug trial can generate inconclusive data that can compromise with the scientific
validation of the results. However these trials are still important to patients, as they
help to determine conditions such as disease-free survival, symptom control, quality

3ARGUMENTATIVE ESSAY
of life, and adverse impact of treatment (Bassler, Montori, Briel, Glasziou, & Guyatt,
2008). The ADAPT trial was stopped due to evidence from APC trial which
demonstrated an increased risk of cardiovascular and cerebrovascular diseases,
among patients that consumed celecoxib and other types of COX-2 inhibitors.
Therefore, early termination of the drug failed to evaluate the effect of conventional
NSAID naproxen sodium and the selective COX-2 inhibitor celecoxib for the primary
prevention of Alzheimer’s dementia (AD) which was the primary study outcome.
Furthermore, truncated trials have been mentioned to overestimate treatment
effects (Bassler et al., 2008). In the ADAPT study, participants who experienced
cardiovascular or cerebrovascular death, MI, stroke, CHF, or TIA in the celecoxib-,
naproxen-, and placebo-treated groups were 28/717 (5.54%), 40/713 (8.25%), and
37/1070 (5.68%), respectively which summed up a hazard ratio (95% confidence
interval [CI]) for celecoxib of 1.10 (0.67–1.79) and for naproxen of 1.63 (1.04–2.55).
Antihypertensive treatment was initiated in 160/440 (47.43%), 147/427
(45.00%), and 164/644 (34.08%) which produced a hazard ratio (CIs) of 1.56 for
celecoxib (1.26–1.94) and 1.40 for naproxen (1.12–1.75) (Martin, 2006). The number
of accrued outcome events was small, but the overestimated treatment effect can be
huge that violates the ethical research requirement of scientific validity. Subsequent
use of overestimated treatment results by clinicians to make clinical decisions also
violates the ethical requirements of social value and violates a favourable risk–
benefit ratio (Murad et al., 2017).
Social Value:
On the other hand, it is very important that investigators comply with the
ethical obligations while dealing with research participants. However, there might be

4ARGUMENTATIVE ESSAY
instances when they neglect obligations towards the society. The tendency of
terminating trials results in insufficient data about other important outcomes that can
jeopardize the wider community for whom the results might be applicable (Murad et
al., 2017). On reviewing the results of the ADAPT trial, some clinicians might
appropriately understand that the benefits of the study drug remain uncertain and
unclear. However, some other clinicians might assume that the hypothesis of the
drug is true and it exposes the patients to the drug whose impact is not testified
within the evidence base. Unknown results from an incomplete trial will greatly
influence the recommendations for clinical practice. Therefore, stopping the ADAPT
trial early is a potential violation of social or scientific value that will mislead the
clinical decision and risk the quality of patient care.
Participant information consent:
There is no doubt that informed consent is one of the most significant
components when conducting clinical trials. Obtaining a consent from a patient for
the clinical trials possesses four features that helps to determine the participant's
decision-making capacity. Obtaining the ethical consent also helps to decide whether
participants have received adequate information in a manner that the person can
understand to decide whether or not to participate in the research and whether the
research is aligned to their individual values and goals (Rajendran, Thomas, Suresh
Madhavan, & Herman, 2019). Informed consent is an ongoing process and
communication that happens between participants and investigators. Participants
should be informed of any changes during the trial by investigators and subsequent
consent should be obtained by the investigators from the participants (Rajendran et
al., 2019). In ADAPT trial, one of the reasons why the trial had been terminated early
was the requisite to inform the participants. The systematic process of stopping a

5ARGUMENTATIVE ESSAY
trial early requires both statistical and medical expertise and the information of
whether or not naproxen and celecoxib can prevent Alzheimer’s dementia (AD) was
not known at the time of terminating the study. Early release of the study results to
the participants compromises a trial’s scientific validity and provide no assurance
that participants would receive accepted treatment or chose to do so based on the
unreliable and risk prone information (Deichmann, Kousel-Wood, & Breault, 2016) .
Additionally, justifications for stopping the trial early not only requires informing the
study participants of the preliminary results but also includes offering them with an
alternative treatment. However, unfortunately, many patients probably would not
have the knowledge or understanding to appropriately interpret the results, which
might lead to disclosing an immature finding to the patients that not only proves to be
misleading but also creates unnecessary public anxiety.
Independent review:
All clinical trials may have termination rules that allow early termination
because of ethical concerns such as the risks to patients outweigh the benefits due
to the occurrence of some unexpected severe adverse events (Murad et al., 2017).
However, terminating a trial early without achieving a scientific valid outcome would
elicit a significant impact on the personal interests. For example, the decision to end
a trial early might result in significant out of pocket costs which is an important
consideration for sponsors since clinical trials are expensive investments. Medical
journals would be interested in reporting the events which could cause increased
public worries. Also, patients and their cares could panic on being a part of the study.
All of these concerns were required to be taken into consideration while undertaking
the decision to stop the trial early (Murad et al., 2017). Consequently, in order to
avoid inappropriate premature termination of trials, rigorous ‘‘stopping rules’’ for

6ARGUMENTATIVE ESSAY
safety monitoring of ongoing trials need to be implemented. These rules involve
much higher-level considerations of harm and benefit as analysed by institutional
review boards and data monitoring committees to undertake a decision whether the
trial should be terminated or not.
In the ADAPT study, for the primary composite endpoint of cardiovascular
death, myocardial infarction and stroke, the existing data showed 17 events in
celecoxib treatment group, 23 in the naproxen arm, and 22 in the placebo. The
hazard ratio for naproxen compared with placebo was 1.57 with 95% confidence
intervals of 0.87 to 2.81, with a p of 0.13. When they added heart failure and
transient ischemic attack into the primary composite endpoint, it generated a
marginally significant p value when comparing naproxen with placebo (Nissen,
2006). Therefore, APADP came to the conclusion that naproxen has a relatively
increased risk of developing cardiovascular and cerebrovascular problems. Without
a confirming regular safety review from DSMB, NIH decided to terminate the ADAPT
trial due to the concern related to the safety of celecoxib in the colon polyps’ studies
(Nissen, 2006). Without a proper explanation of the term of cardiovascular and
cerebrovascular events and the number of events that happened, NIH failed to
recognize that ADAPD was an entirely contrasting study that evaluated different
outcomes for different targeted patients, even though they were using the same drug
(Nissen, 2006). Therefore, there could be a possibility that extending the trial could
help in gaining valuable knowledge that would prevent Alzheimer Disease and
sudden termination of the ADAPT study would then would be an incorrect decision.
Since all clinical trial studies have their particular study entry criteria when
designing a trial, it is important to consider the characteristics of patients when
recruiting—particularly their age, sex and major risk factors or diseases (Schwartz, &

7ARGUMENTATIVE ESSAY
Woloshin, 2005). ADAPT study was designed to investigate conventional impact of
NSAID naproxen and selective celecoxib for prevention of Alzheimer’s dementia
(AD). The main selection criteria included the age of 70 years or older with a family
history of Alzheimer’s dementia. Participants underwent cognitive screening to
exclude those with dementia or other cognitive disorders. In order to assess their
risks of experiencing cardiovascular and cerebrovascular conditions appropriately,
participant’s age, sex and lifestyles should be taken into consideration. Patients aged
over 70 years or leading unhealthy lifestyles would be placed at a higher risk of
experiencing stroke or heart attack on account of unhealthy lifestyle factors
(Schwartz, & Woloshin, 2005).
Likewise, accidental injuries and death are sometimes seen in subjects
enrolled in clinical trials despite following strict study protocols (Ghooi, 2013). Any
serious adverse events must be reported to on-site primary investigators to
determine the causality and also be reported to the institutional review board for the
review process. The most common cause of injury and death within an experimental
trial is due to exacerbation of pre-existing disease (Ghooi, 2013). If extending the
trial results in death, the cause of death should be further investigated to determine
the relevance of the study drug. Different people face different risks that might cause
death. The reason for death might not only be because of their participation in the
trial but also because they have different medical histories and different
environmental exposures. Consequently, ADAPT study could benefit from a large
group of patients with Alzheimer’s Dementia (AD). Death alone should not be the
reason for stopping clinical trial from extension, the decision on extension of the trial
should be made along with all other factors and must be decided upon by members
of the institutional review board (Carlisle, Kimmelman, Ramsay, & MacKinnon,

8ARGUMENTATIVE ESSAY
2015). Furthermore, based on the data available from the ADAPT trial, naproxen did
show a suggestive increase in the incidence of cardiovascular and cerebrovascular
risk. Therefore, in case of an extension of the trial the eligibility criteria must be
amended. The patients’ medical and surgical histories, existing cardiovascular and
cerebrovascular risk should be taken into account and excluded from the study. An
updated information consent form where potential risks are clearly outlined for
participants should be submitted to institutional review board for the purpose of
review. All involved research professionals at all sites must undergo comprehensive
trainings in order to choose and monitor participants on a regular basis (Carlisle,
Kimmelman, Ramsay, & MacKinnon, 2015).
Conclusion:
In a nutshell, the paper critically identified the ethical issues in the ADAPT
trial. Early termination of the trial has questioned the scientific validity of the trial and
has potentially misled current clinical practice. The impact of the same could lead to
informing patients with unreliable results. This aspect has compromised with the
scientific validity and has furnished no proof on patients’ welfare. The paper also
discussed why it was an incorrect decision to stop the ADAPT trial even though
extending the trial could have helped in gaining valuable knowledge that could
prevent Alzheimer’s disease. While extending the trial would result in deaths of
certain participants, the process of extending the trial could only be made after all
members from the instructional review board thoroughly reviewed the trial
subsequently so as to ensure that the study adhered with the ethical principles.

9ARGUMENTATIVE ESSAY

10ARGUMENTATIVE ESSAY
References:
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stopping of randomized clinical trials for overt efficacy is problematic. Journal
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question are commonly published after a trial stopped early for benefit.

11ARGUMENTATIVE ESSAY
Journal of Clinical Epidemiology, 82, 12-19.
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