Prescribing Experimental Drugs – A Conflict of Informed Consent

PRESCRIBING EXPERIMENTAL DRUGS

A Conflict of Informed Consent

Michael Regidor

Medical Ethics, Section 4

Professor Bradshaw

October 1. 2010

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Prescribing Experimental Drugs – A Conflict of Informed Consent

Prescribing Experimental Drugs:

A Conflict of Informed Consent

Hypothesis:

Informed consent has ascended to the pinnacle of ethical norm for medical intervention
for treatment or research purposes. This norm has become a legal precedent and a tool to counter
autocratic and paternalistic medical practices. Yet debate about the implementation of informed
consent is narrow and polarizing, centering on the right of individuals to be fully informed and to
freely choose versus an autocratic, paternalistic practice that negates individual choice.

The principles behind informed consent are based on understanding the relevant
information about the disease, the treatment options, and the recommendations of the physician;
evaluation of that information to form a framework of values that will enable the patient to judge
whether a particular health care decision will accomplish what he considers good for himself;
and reasoning and deliberation on all available courses of action which will likely affect him1.

These principles “conflict” with clinical research methodologies as they relate to

experimental drug treatment, such as blinded or randomized trials where the participants are
assigned at random to groups that either receive the new drug, receive the standard treatment for
that disease, or receive a nonfunctional substitute, such as a sugar pill. This last group is often
called the control group, or the placebo group. The participants in randomized trials usually do
not know which group they will belong. Randomization is also a way to help ensure that
different groups in the trial have similar characteristics making it easier to compare outcomes
between the groups. In blinded clinical trials, neither the physician nor the trial participant knows
whether the participant is receiving the experimental treatment. It appears to be counterintuitive
to participate in clinical drug treatment trials based on the methodologies used in the research
process. Is the information that is provided to the participants in a clinical trial enough to
constitute informed consent?

Introduction:

What is informed consent?

Informed consent is the personal exchange between physician and patient. The physician
provides information so the patient becomes “informed”, and the patient then consents to the
proposed treatment. The patient then signs a form indicating the consent for the procedure. The
legal background of informed consent sets forth the two major elements of the informed consent
doctrine: information and consent. Physicians will tell patients their medical diagnosis and the
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prognosis if nothing is done. Physicians must make sure their patients understand what is wrong
and what will happen if the condition is not treated. Additionally, physicians will tell patients
about all the medically accepted treatment options for their condition, as well as the risks,
burdens, and benefits associated with each. There is temptation for physicians to neglect
disclosure of the burdens because they are naturally reluctant to discuss comprehensively the
burdens and possible side effects of interventions that they feel the patient really needs. Yet the
patient needs this information if her consent is going to be truly informed. The requirement that
physicians disclose all medically accepted treatments also means that the physician may have to
provide information about treatments he does not favor or cannot provide, i.e. experimental
clinical trials. Physicians will also recommend treatment plans and give the reasons why they
think it is best for the patient.2

To give consent, an individual must act autonomously without constraint, coercion or

manipulation. The freedom to choose what is best for one’s self when all information is gathered,
digested, and understood, can a decision of consent be made.

Clinical Trial Process

Clinical trials are designed to test whether a drug is safe for humans, and whether the
drug is effective in treating human diseases or conditions. Although the drug has generally gone
through extensive animal testing before human trials begin, animal trials cannot always predict
how new medicines will affect humans. Even the most painstaking tests with animals give only
approximate indications of how people will respond to drugs. At some point, after thorough
study in animals and when the Food and Drug Administration (FDA) is convinced human
experimentation will be safe, tests with humans become necessary.

There are currently four phases in which a drug must be tested prior to being approved
for the public.3 Phase IV clinical testing will not be discussed here since it involves trials after a
new drug has been approved.

Phase I. This is the first major stage in the clinical testing process. The drug is
administered to a small group of subjects in an inpatient clinic, where the subjects can be
monitored constantly. The main purpose of Phase I trials are to subject the participants to the
drugs to determine levels of toxicity and, when appropriate, pharmacologic effect and followed
by early dose-ranging studies in patients for safety and in some cases for early evidence of
effectiveness. Alternatively, with some new drugs, for ethical or scientific considerations, the
initial introduction into humans is more properly done in selected patients. Often healthy people
are enrolled in Phase I trials rather than patients on the assumption that if the drug has
unexpected side effects, healthy people have the best chance of escaping permanent harm. But on
occasion, as with a drug treating a serious disease like cancer, Phase I subjects may be patients
who have failed standard treatments.

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Phase II. After a drug’s initial safety has been established, Phase II trials are commenced.
In this stage, the drug is administered to a larger group of people, allowing further study of a
drug’s effectiveness and relative safety. The main purpose of Phase II testing is to determine a
drug’s efficacy or whether its effect on the body is significant enough to warrant further testing.
Normally, these are performed on closely monitored patients of limited number.

Phase III. This is usually the last stage prior to approval of the drug. These trials involve
large subject groups and are designed to be the final assessment of a drug’s efficacy and side
effects. These are performed after effectiveness has been established, at least to a certain degree,
and are intended to gather additional evidence of effectiveness for specific indications and more
precise definition of drug-related adverse effects. Phase III trials go one step further by
comparing the drug candidate to the current standard treatment for a particular condition. If a
drug is effective but shows no significant benefits over a treatment already in use, it can still be
approved for production.

Informed Consent in Clinical Research

The process of obtaining informed consent from potential clinical trial participants is a
critical point of entry in the beginning phases of clinical research trials. Although the basic
principles of obtaining informed consent transcend therapeutic areas and vulnerable patient
populations, significant differences must be considered when research designs include
individuals at increased risk. Special attention must be given to meeting the needs of vulnerable
populations, such as children, the terminally ill, or the mentally impaired.4 Typically, the
introduction of a potential subject to a clinical trial occurs in one of the following ways:

• The subject may have been identified as part of a recruitment campaign

• The subject may simply be part of a patient population being studied
• The clinical trial may be offered as a treatment option after a patient has been
given the facts concerning a diagnosis and prognosis.

Although there are several ways that patients learn about clinical trials, little is known
about the factors that influence the decision to participate in scientific research5. Kuczewski and
Marshall recommend adopting the approach that consent is an interactive and dynamic process
and many factors can influence the study participant’s willingness to sign the document. These
factors include socioeconomic background, cultural traditions, literacy and language ability, and
interactions with physicians and other healthcare professionals.

The informed consent process is based on complete disclosure of the facts. Ethical
guidelines direct those involved in obtaining consent to insure that participation should be
reached after the subject has reviewed and considered the information given, and freely chosen
whether or not to participate. Written information detailing the possible side-effects and risks
that could be incurred as well as information about the randomization process and other aspects
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relating to trial participation must be disclosed. Additionally, a distinction must be made as to

their understanding of what is research and what is routine medical therapy.6

DISCUSSION AND ANALYSIS: ARE PARTICIPANTS TO EXPERIMENTAL DRUG

TRIALS REALLY AUTONOMOUS TO THE POINT OF GIVING INFORMED
CONSENT?

Randomized Blind Clinical Trials

The randomized double blind process is standard, preferred practice for drug trials. For
“adequate understanding” to take place, patients need at the very least to be aware why they are
being randomized and, if there is a placebo group involved, that there is a chance that they will
not be receiving an active treatment. However, in numerous studies, trial subjects poorly
understand the process of randomization in clinical drug trials.7Clearly, if the patient is placed in
the placebo group, the use of placebo in therapeutic medication clearly violates the principle of
autonomy and informed consent. It is standard in modern writing on medical ethics to oppose
placebo use because it represents a specific instance of the more general issue of patient
deception. The value of avoiding deception is grounded in the more basic values of the autonomy
and dignity of the individual patient. The basic idea is that of moral reciprocity. 8,9,10 We generally
wish that other people treat us in a manner that shows their respect for us as persons; and this
entails that they not use manipulation or deception on us, even if they judge the results to be for
our own good. If we are to regard patients as moral equals and to respect their dignity as persons,
we are prohibited from practicing deception or manipulation, as in the case of clinical drug trials.

Deceptive or not, placebos have in fact been widely administered by practicing

physicians and investigators and to many the fascinating power of the body to respond to purely
symbolic interventions seemed too potent a therapeutic tool to pass up. It has become clear that
whatever happens when a patient gets better after digesting a placebo, also happens to some
degree whenever the patient receives a pharmacologically potent treatment within a supportive
healing relationship; that at least some of the symptom relief that follows administration of the
active treatment arises from the emotional and symbolic factors. This phenomenon called the
“placebo effect” pervades much of medical practice even when no placebo has been used.11 Thus,
it is noteworthy that there has been relatively little attention devoted to whether and how
treatments tapping the placebo effect, deriving from patient expectations or conditioning, can be
administered without deception.

Therapeutic Misconception

The prevailing ethical perspective on clinical trials holds that physician-investigators can
discharge their “therapeutic obligation” to patients in the context of randomized clinical trials
(RCT) as long as treatments being tested scientifically satisfy clinical research methodologies.
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This perspective is fundamentally flawed. An ethical framework that provides normative

guidance about a practice should accurately characterize the practice. The prevailing ethical
perspective fails this test: All sound ethical thinking about clinical research, and the regulatory
framework for review of protocols for clinical investigation, depends on a basic distinction
between research and therapy. But the claims in the prevailing ethical perspective on clinical
trials conflate research and therapy. These claims are that the ethics of the physician-patient
relationship must govern RCT’s that physicians who conduct these trials have a “therapeutic
obligation” to patients enrolled in them, and that RCT’s must be compatible with some form of
“clinical equipoise”.12

“Clinical Equipoise” in the scope of medical research and clinical trials, demands that at
the time a clinical trial is being carried out, there be a state of genuine scientific uncertainty in
the medical community over which drugs or treatments being tested is more efficacious and
safer.12,13 Sometimes, the question of whether clinical equipoise exists in a clinical trial is not so
obvious. This situation sometimes crops up in clinical trials for cancer. An example of whether
clinical equipoise exists, an article written for the New York Times as a front page human
interest story was published on September 18, 2010. In the article, reporter Amy Harmon
highlights the issue of clinical equipoise in a clinical trial for a new drug for melanoma that
shows great promise. In brief, it is the story of two cousins, one of whom is receiving the new
“wonder drug” in a clinical trial and one of whom is receiving the current standard of care for
stage IV melanoma, which has very little effect in prolonging life;

“And when, last year, each learned that a lethal skin cancer called melanoma was
spreading rapidly through his body, the young men found themselves with the shared chance of
benefiting from a recent medical breakthrough.

Only months before, a new drug had shown that it could safely slow the cnacer’s
progress in certain patients. Both coursins had the type of tumor almost sure to respond to it.
And major cancer centers, including the University of Claifornia, Los Angeles, were enrolling
patients for the last, crucial test that regulators required to consider approving it for sale.

“Dude, you have to get on these superpills,” Thomas McLaughlin, then 24, whose
melanoma was diagnosed first, urged his cousin, Brandon Ryan. Mr. LcLaughlin’s tumors had
stopped growing after two months of taking the pills.

But when Mr. Ryan, 22, was admitted to the trial in May, he was assigned by a computer
lottery to what is known as the control arm. Instead of the pills, he was to get infusions of the
chemotherapy drug that has been the notoriously ineffective recourse in treating melanoma for
30 years.

Even if it became clear that the chemotherapy could not hold back the tumors advancing
into his lungs, liver, and most painfully, his spine, he would not be allowed to switch, lest it
muddy the trial’s results.”
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It is tragic that Mr. Ryan died during the trial of a very promising drug after being
randomized in a control group of a standard therapy that is known to be ineffective. If it turns out
that the risks of one therapy strongly outweigh the benefits of the other, or the benefits of one
therapy strongly outweigh the risks of the other, the study is said to fall out of equipoise, Why
then wasn’t the effective treatment given to the vulnerable control group?

Certainly, investigators and ethicists recognize that clinical trials are scientific
experiments, which differ from standard medical care. They also recognize that they are subject
to regulatory requirements which do not apply to routine medical practice. However, the
prevailing ethical framework views clinical trials through a therapeutic lens. The mainstream
ethical approach to clinical trials attempts to have it both ways; to view the clinical trial as a
scientific experiment, aimed at producing knowledge that can help improve the care of future
patients, and as treatment conducted by physicians who retain fidelity to the principles of
therapeutic beneficence and therapeutic non-maleficence that govern the ethics of clinical
medicine.

The therapeutic misconception in the ethics of clinical trials is reflected not only in the
language commonly used within the clinical research enterprise, but also in the “similarity
position”. Clinical trials are often described as “therapeutic research” and investigators are
regarded as having a “therapeutic intent”. Research participants who are being studied because
they have a medical condition under investigation are referred to as “patients” and investigators
as “physicians or doctors” without qualification. In the “similarity position”, the ethics of clinical
trials rest on the same moral considerations that underlie the ethics of therapeutic medicine. 12

CONCLUSION:

In writing this research paper, I have come across a wide array of articles and
publications profusely describing the conflict between informed consent and clinical research
trials. There are pros and cons across the spectrum of the medical community as to whether
informed consent in the setting of clinical trials is a valid process in determining the autonomy of
the patient/participant. On the one hand, it is an ethical imperative to promote the values of
personal well being and self determination. The patients’ right to determine his or her heath care
is widely recognized in ethical theory as well as the protection from exploitation and harm.

On the other hand, the scientific community, whose basis for clinical trials relies on the
voluntary consent of the human subject as absolutely essential, the methodologies and the
process of obtaining informed consent from the patient conflict with the theory of being “truly
informed” and “truly autonomous”. The randomized double blind process in clinical trials, is a
misleading indicator of patient/participant understanding. By “not knowing” or at the very least
having an “adequate understanding” of why they are being randomized and by receiving a

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placebo versus the active treatment, there is certainly not enough information or disclosure to
truly determine informed consent.

METHODOLOGIES USED:

In the writing of this paper, the theories, principles and processes of informed consent
and scientific clinical research were compared. This includes the process and principles of
informed consent in a traditional patient-physician basis and the process and principles of
informed consent in a scientific clinical trial basis between patient/participant -
“doctor”/researcher/investigator. In conducting the research to determine conflicts of informed
consent within clinical research trials several subject areas were identified that posed compelling
arguments including the following:

• Informed Consent in Clinical Research

• Ethics and Clinical Trials
• Ethics and Informed Consent
• Placebos and Clinical Trials
• Access to Experimental Treatment
• Clinical Equipoise and Ethics
• HIV/AIDS Research - History and Methodologies
• Abigail Alliance for Better Access to Developmental Drugs v. Von Eschenbach
• FDA Regulations and Clinical Trials
• Therapeutic – Non Therapeutic Misconception of Clinical Trials

Disclosure of information varies between the two situations, providing the basis for conflict in
informed consent.

Additionally, case studies such as Abigail Alliance for Better Access to Development Drugs v.
Von Eschenbach; the HIV/Aids Research in Developing Countries14; and the Ryan/Mclaughlin
article (cited), were read as part of better understanding the controversies and benefits of clinical
drug trials.

REFERENCES:

1. R.J. Devettere, “Practical Decision Making in Health Care Ethics” (2010, p73).
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2. R. J. Devettere, “Practicial Decision Making In Health Care Ethics”, (2010, pp75-79).

3. Code of Federal Regulations, Title 21, Subpart B 312.21

(http://ecfr.gpoaccess.gov/cgi/t/text/text-idx?
c=ecfr&sid=2a88f275a8609a20ed3f25adbeb7205f&rgn=div5&view=text&node=21:5.0.
1.1.3&idno=21#21:5.0.1.1.3.2.1.2).

4. R.J. Devettere, “Practical Decision Making in Health Care Ethics” (2010, pp86-87,
pp105-117).

5. M.G. Kuczewski, P. Marshall, “The Decision Dynamics of Clinical Research: The

Context and Process of Informed Consent”, Medical Care, 40 (9Suppl) 45-54 (2002).

6. J.P Kahn, A.C. Mastroianni, “Moving From Compliance to Conscience: Why We Can
and Should Improve on the Ethics of Clinical Research, “Archives of Internal Medicine,
161 (7) 925-8 (2001).

7. Cassileth et.al. 1980; Jan and Demets, 1981; Sonwdon et.al. 1997.

8. T.H. Beauchamp, TH, Childress, JF, “Principles of Biomedical Research”, New York:
Oxford University Press; 1979.

9. H. Brody, “Ethical Decisions in Medicine, 2nd Ed. Boston; Little, Brown & Co; 1981.

10. B. Simmons, “Problems in Deceptive Medical Procedures: An Ethical And Legal

Analysis of the Administration of Placebos. J of Medical Ethics 1978; 4:172-81.

11. Brody, H. Waters DB. “Diagnosis is Treatment”. J Family Practice; 1980; 10:445-9

12. F.G. Miller, H Brody, “ A Critique of Clinical Equipoise: Therapeutic Misconception in

the Ethics of Clinical Trials”; Hasting Center Report 33. No. 3 (2003): pp19-28.

13. D. Gorski MD, “Clincial Equipoise Vs Scientific Rigor in Cancer Clinical Trials, Science
Based Medicine, (Sept 20, 2010), (http://www.sciencebasedmedicine.org/?page_id=224)

14. R.J. Devettere, “Practical Decision Making in Health Care Ethics” (2010, pp380-
383;471-482).

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