the ethical dilemmas of clinical trials - long
- From: J <nexsw@nvalid,anon>
- Date: Mon, 13 Aug 2007 19:29:07 -0400
< http://www.curetoday.com/currentissue/features/feature2/index.html >
In Whose Best Interest?
Exposing the ethical dilemmas of clinical trials reveals a balance between
researchers wanting to advance medicine, drug companies wanting to get
their drug to market, and patients wanting to live.
By Heather L. Van Epps, PhD
Mark Origer almost didn?t live to walk his daughter down the aisle. At 47,
he was diagnosed with metastatic melanoma, one of the deadliest forms of
cancer, and did not respond to any treatment. Origer was out of options.
Without treatment, he was given six months to a year to live. But
conversations with his oncologist and Internet searches with his wife led
Origer to the National Cancer Institute, where Steven Rosenberg, MD, PhD,
and his team were using an experimental gene therapy to treat patients
with late-stage melanoma. Origer was enrolled in Dr. Rosenberg?s trial,
and the radical treatment?which involved removing tumor-fighting T cells
from Origer, engineering them to be better killers, and re-infusing them
back into his body?is working. Now 54, he has been disease-free for more
than two years, and walked his daughter down the aisle in fall of 2005.
Most patients who participate in a clinical trial don?t have such dramatic
success stories. Rebecca Dinning?s clinical trial experience began only
after her breast cancer was successfully removed in a bilateral
mastectomy. Dinning, who was diagnosed in July 2005 at age 31, is now
participating in the ongoing TEXT (Tamoxifen and Exemestane Trial) study,
aimed at determining which drug is better at preventing breast cancer from
returning. But no matter the outcome, clinical trials like these are
essential for the development of lifesaving cancer therapies.
Simply put, clinical trials are experiments, and thus the primary purpose
of these trials is to learn whether a new drug or treatment is safe and
effective?not primarily to benefit the patient. This fact raises many
ethical questions. When, for example, is it appropriate to use patients as
experimental subjects? And how are the rights of patients protected? These
questions arose dramatically 60 years ago in Nazi Germany, when
concentration camp prisoners were subjected to tortuous experiments
without their consent. These atrocities prompted a set of ethical rules
called the Nuremberg Code, which protects the rights of people who
participate in human research.
The Nuremberg Code and later guidelines, such as The Declaration of
Helsinki (1964) and the Belmont Report (1979), require informed consent,
meaning participants must volunteer with a full understanding that they
are participating in research and understand why the research is being
done and all the potential benefits and risks that go along with it. The
patient can end participation in a trial at any time, for any reason, and
a trial?s design must be scientifically rigorous with every attempt to
minimize harm and adequately monitor patients.
Even with built-in safeguards, there are many ethical issues for cancer
patients to consider before deciding to enter a clinical trial. For
Origer, the decision was easy. ?My tumor was growing, and more tumors had
shown up in my lungs. It was either try something radical or go home and
die.? Ethical issues, Origer says, never entered his mind.
Dinning also spent little time debating whether to enroll, as both
tamoxifen and Aromasin® (exemestane) had already been shown to boost
survival in breast cancer patients. Even though the chances were good that
her cancer would not return, she was still anxious over which drug would
be more effective.
But the decision is not always so easy, and it can also be hard for
patients to decipher what they should and shouldn?t worry about. The
emotion that often surrounds a cancer diagnosis doesn?t help, says Ezekiel
Emanuel, MD, PhD, chair of clinical bioethics at the National Institutes
of Health. ?[Patients] are not the most level-headed at this time, and
they cannot be expected to defend their own interests.?
To Enroll Or Not to Enroll
Since patients may not be able to adequately uncover a trial?s pros and
cons, the responsibility falls largely to research physicians, who must
educate patients about the scientific goals, potential risks, possible
benefits of the study, and the alternatives to not participating as well
as a reassurance that their refusal to participate will not affect their
care. ?You?ve got to be able to tell patients what is really important and
what is likely [to happen],? says Dr. Emanuel. And this information varies
depending on the type of clinical trial.
Phase I trials, for example, are designed to determine how high a dose of
the experimental drug can be given and whether it has any side effects.
Because phase I trials typically enroll patients whose tumors are
resistant to available therapies and aren?t designed to measure if the
drug is effective, the response rate in phase I trials is generally low,
meaning the chances are small that a patient?s cancer will respond to the
treatment.
Critics argue the unlikelihood of benefit makes early trials inherently
unethical, even if the patient consents to participate. ?My main concern
with phase I trials is how well the patient understands the potential for
benefit,? says Steven Joffe, MD, pediatric oncologist at Dana-Farber
Cancer Institute who conducts research on the ethics of clinical trials.
?It?s the patient who says, ?I?m probably going to get better? and then
makes a decision based on that belief that worries me.?
This type of misunderstanding, known as ?the therapeutic misconception,?
is common, perhaps because the normal doctor-patient relationship is
focused solely on improving the health of the patient, whereas the primary
goal of a clinical trial is to answer a scientific question.
With such a low potential for benefit, figuring out why a patient would
enter a phase I trial relates in part to the type of patients who are
eligible. They have a life-threatening cancer and have typically not
responded to conventional treatment. This feeling of desperation may lead
patients to feel ?their only other options are unproven therapies or
palliative care,? says Dr. Joffe.
Patients eligible for phase I trials may be reassured by a recent study
published in the New England Journal of Medicine that reported a higher
potential for benefit in phase I trials than previously thought?around 11
percent of patients benefited compared with earlier estimates of 4 to 6
percent. This is in part because phase I trials include not only
traditional dose escalation studies of single drugs, but also new
combinations or dosing schedules of FDA-approved drugs.
Rarely, phase I trials have astounding results, such as the 93 percent
response rate in chronic myeloid leukemia patients treated with Gleevec®
(imatinib). The drug was extremely effective because scientists identified
the protein that caused CML, and the drug was designed to block that
protein.
Phase II trials continue to test the safety of a therapy, but also begin
to evaluate how well a new treatment works in a selected tumor type. Phase
III trials, which are designed to compare the new drug with the best
current treatment, raise their own set of tricky ethical issues.
Participants in phase III studies are randomly assigned to receive the
conventional treatment, the investigational treatment, or, occasionally, a
placebo if no standard exists. Some doctors argue randomization is
unethical, as half the patients are denied a possibly more effective
therapy. Randomized trials, currently the most accurate way to determine
outcome of an experimental therapy, operate on the principle of clinical
equipoise, a genuine uncertainty about which treatment will be more
beneficial.
?I think the greatest difficulty comes up when patients are really hopeful
that they will get the experimental therapy,? says Dr. Joffe. ?But
randomization is essential to ensure we come away with a definitive answer
as to which treatment is better.? Indeed, many patients worry about being
randomly assigned, and some opt out of trials because they want to be in
control of their treatment.
?I did wonder if I would prefer one [treatment arm] over the other,? says
Dinning. ?But I really couldn?t come to a decision over which one I hoped
to be in.? Dinning was indecisive because she knew both drugs were already
known to be effective. She also had altruistic motives. ?If [the trial]
helps progress our knowledge as a cancer community, then it is definitely
worthwhile,? she says, adding with a laugh, ?but I?m not so altruistic
that I?ll hop on any clinical trial that comes along.? Dinning ultimately
found out she had been assigned to the Aromasin arm.
Another important point for patients to understand about phase III studies
is if they fall outside the research parameters for any reason during the
study, they must leave the trial. ?You have to stick to the protocol,?
says Richard Klein, of the Human Subjects Protection Liaison Committee at
the FDA. ?The protocol sets the eligibility requirements to enter a trial
so that participants share similar characteristics, such as type of
cancer, stage of disease, and other existing medical conditions. This
consistent patient profile is important when it comes to analyzing trial
data to determine which treatment is more beneficial. The treatment of the
individual is secondary to the research goals of the trial.?
Newer study designs may ease some of the fears and criticisms of
randomization. Bayesian design, for example, allows for the design of
trials to be evaluated and modified according to early data from a study.
This may not change things for those who start a trial and are later
excluded, but it might allow more patients to be randomized into the
treatment arm that appears more beneficial as a trial progresses.
Eligibility criteria can also be modified to favor patient groups that
have responded better in an ongoing trial.
Regardless of the trial?s phase, ?the small chance of a response provides
important hope to patients,? says Martin Abeloff, MD, chair of the ethics
committee for the American Society of Clinical Oncology and director of
the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. ?Patients
also realize they are helping drugs be developed that will help other
people.?
The Placebo Predicament
In some circumstances, a patient may be eligible for a placebo-controlled
trial. The use of placebo raises the hackles of many critics, who don?t
agree with the justification for withholding treatment from patients with
a life-threatening illness like cancer.
Patricia Delaney, director of the FDA?s Cancer Liaison Program and herself
a cancer survivor, is a staunch defender of placebo-controlled trials. She
says placebos are only used when no proven effective treatment is
available for a specific group of patients. The anti-placebo argument,
says Delaney, is an overly emotional one.
?It gets characterized as, ?How can you keep a potential cure from me??
This is a very emotional position that, so far, has not prevailed,? mainly
because there?s no basis for comparison, no meaningful conclusion that can
be reached about the benefits, if any, to be gained from a test therapy.
Delaney emphasizes the experimental drug might shorten rather than extend
survival or could negatively impact quality of life.
Placebo-controlled cancer treatment trials are only conducted in the
United States in cases where no other treatment has proven effective, and
in some prevention trials that test how well a drug or treatment prevents
cancer from recurring. Two recent examples are the trials for Vectibix?
(panitumumab) for metastatic colon cancer and Nexavar® (sorafenib) for
primary liver cancer. In both trials, patients receiving placebo were
switched to the treatment arm of the study as soon as the drug was shown
to be effective.
Dr. Abeloff appreciates the unique benefits of placebo-controlled trials.
?There are some organizations that use placebo-controlled trials to
demonize clinical research,? he says. ?This is totally unproductive.? But
he points out the number of placebo trials are decreasing as the number of
proven, effective cancer treatments expand.
Considering Conflict
As if all of this wasn?t enough for patients to think about, they should
also be aware of potential conflicts of interest of those carrying out the
trial.
The physician running the trial, for example, might own stock in or be a
paid consultant for the company whose drug is being tested. Physicians are
also motivated to publish their findings and advance their careers by
enrolling a higher number of patients. Or the hospital conducting the
study might receive payments from a drug company for each patient enrolled
that covers or exceeds the costs of conducting the trial. These financial
ties can create a motive for the physician to enroll as many patients as
possible in the study or?of greater concern?a vested interest in the
trial?s outcome.
Federal guidelines encourage but do not require disclosure of potential
financial conflicts of interest to the patient. But some physicians feel
?encouraged? disclosure is not enough. ?No physician should ever be
involved in making decisions in clinical trials if they have a financial
interest in the outcome [of the study],? says Dr. Rosenberg. ?When it
comes to evaluating experimental treatments, this should be an inviolable
rule.?
Most clinical trials are run by academic research institutes or the
government, which carefully monitor studies at every stage?from the study
design to the treatment protocol to data collection and close examination
of any conflicts of interest that exist with the physician and the drug
company. Research conducted directly by a drug company falls under the
FDA?s jurisdiction.
Drug companies may stack the deck in their favor when it comes to testing
drugs they manufacture. A 2007 study of breast cancer trials published in
Cancer found that pharmaceutical industry-funded trials have favorable
results more often than non-industry funded trials. Authors of the study
addressed possible reasons for the finding, including ?the pharmaceutical
industry may be more inclined to support or design smaller, single-arm
studies for patients with advanced breast cancer [that] likely reflects
their important role in the development of novel therapeutics ? [and] in
general, positive studies are more likely to be published than negative
studies (publication bias).?
Investigators also clarified that cooperative group (non-industry) trials
typically answer other crucial questions, such as optimal dose,
toxicities, and duration of therapy?questions not necessarily at the top
of the list for a drug company trying to get its drug approved.
Although many potential conflicts exist, they seem to be of little concern
to patients. According to a study published last year in NEJM, most
patients in cancer research trials are not worried about financial ties
between doctors or research institutes and drug companies. For most of the
patients, having that information would not have changed their minds about
enrolling in the study. This indifference stemmed, in part, from the
belief, which was indeed true, that oversight systems are in place to
manage these types of conflicts and protect their interests as patients.
Nevertheless, patients should check informed consent forms for disclosure
of financial interests. If they don?t see them, they should ask.
Communication Is Key
The many ethical issues surrounding a patient?s decision to enter a
clinical trial may seem overwhelming. Perhaps the most effective way for a
patient and their family to grapple with these issues is by communicating
with the doctors conducting the research trial. Dinning gives her
oncologist glowing reviews. ?As long as I had questions, I felt like he
didn?t have anywhere else to be,? she says.
And Origer praises Dr. Rosenberg?s team at the NCI. ?They did a good job
of prepping me as far as what to expect [from the therapy],? he says.
?They didn?t raise my hopes unnecessarily and were very honest and
upfront.?
?I?ve had a very positive experience,? says Dinning, ?but all patients
need to make their own decision on whether a trial is something they need
to do.?
Origer certainly has no regrets. ?It saved my life.?
.
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