e-Ethics December 2002
Research or Marketing? Ethical Considerations in Phase IV Research
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Today Dr. O'Hara, who is a
community-based physician,
received two invitations to enroll
patients in research.
Lotsapharma wants to "learn
more about Ossalube," an expensive
arthritis medication recently
approved by the Food and Drug
Administration (FDA). If Dr. O'Hara
participates, his patients will receive
free Ossalube for six months. After
any office visit a study patient makes
during that time, Dr. O'Hara will
complete a one-page questionnaire
concerning vital signs, range of
motion, and other data. He will
receive $2,000 for each patient he
enrolls, plus an additional $5,000
if he recruits thirty patients in sixty
days. Lotsapharma's invitation
includes a journal article noting
positive preliminary findings of
Ossalube's efficacy and a final
reminder that patients will receive
the drug for free. A contract
research organization (CRO) processes
all paperwork; except for returning
questionnaires, Dr. O'Hara will
not submit any other documents.
The second invitation is from
Mightymed. Its medication,
Cardevac, lowers cholesterol and
high blood pressure with a single
pill taken once daily. Mightymed
wants more information about
patient adherence, tolerability, drug
interactions, and incidence of side
effects. Its letter summarizes Phase
III (pre-approval) study results,
including Cardevac's safety profile,
and explains that, after signing a
consent form describing the study's
purpose, and risks and benefits of
study participation, patients will
receive one month's supply of
Cardevac. Each patient will visit Dr.
O'Hara monthly, return the Cardevac
bottle and any unused pills, and
obtain another month's supply. At
each visit a small amount of blood
will be drawn and sent to an independent
lab; both Dr. O'Hara and
patients will complete questionnaires.
Dr. O'Hara will summarize
his exam, noting twelve specific clinical
findings (weight, blood pressure,
etc.). Patients will answer
questions regarding physical activities
and the ease or difficulty of taking
Cardevac. A CRO manages the
study, but Mightymed allows local
IRB review. Dr. O'Hara will receive
$300 for each office visit to cover
time spent with patients, the blood
draw, and processing consent forms
and questionnaires. The consent
form advises patients that they
should not be billed for office visits,
lab work, questionnaires, or
Cardevac since Mightymed covers
all research-related expenses.
Both studies sound intriguing.
How should Dr. O'Hara respond?
Discussion
Dr. O'Hara's interest in these
projects is understandable. The
importance of Phase IV research is
well established. Sometimes
referred to as post-marketing
surveillance because it occurs after
FDA approval, Phase IV research
provides opportunities to study
dosage, drug interactions, and
adverse events in larger populations
over longer periods of time and in
more natural settings than are typically
available in Phase III research.
Sometimes FDA approval is conditioned
on Phase IV completion in
order to confirm or change the safety
profile of the drug (or medical
device or procedure).
Phase IV studies represent part
of an overall increase in industry-sponsored,
office-based research.
From 1991 to 1998 the proportion of
pharmaceutical industry clinical
research funding allocated to academic
medical centers dropped
from 80% to 40%, whereas the number
of private physicians conducting
clinical research tripled between
1990 and 1997.
1
It is therefore critical
that Dr. O'Hara understand ethical
issues in clinical research, especially
those with particular importance for
Phase IV studies.
The following questions should
frame Dr. O'Hara's deliberations:
Is it research or marketing? All
research, including Phase IV studies,
requires a properly designed
protocol with clear, obtainable
objectives that can contribute to
generalizable knowledge. Thus
Mightymed has described how the
Cardevac study will augment knowledge
gained in previous studies.
But some manufacturers call marketing
strategies "research" in an
effort to influence prescribing practices
by means other than direct
advertising and sales calls. While
Mightymed identifies regular points
when explicit data are collected from all
subjects, Lotsapharma's "study" is completely
open ended. In fact, Dr. O'Hara
could give Ossalube to patients who
make no follow-up office visits—and
supply no data for the "research."
Are the incentives appropriate?
Propriety of physician incentives is
determined less by their amount or
value than by the purposes to which
payment is applied and, in some cases,
its form. If Dr. O'Hara enrolls thirty
patients into the Lotsapharma study
within two months, the $65,000 he
will make seems grossly disproportionate
to the time and effort required.
Mightymed's reimbursement appears
much more in line with resources
required to complete the protocol.
Furthermore, Mightymed has anticipated
the ethical problem of "double dipping,"
which would enable Dr. O'Hara to
bill patients for research activities and
be reimbursed by the sponsor.
(Although not at issue in this case, compensation
in the form of stock or stock
options would be ethically problematic,
as would Dr. O'Hara's holding a proprietary
interest in Ossalube or Cardevac.)
Are subjects adequately informed
and protected? Lotsapharma's omission
of informed consent is serious. Patients
could take Ossalube without knowing
they are research subjects. The obligation
to inform subjects of distinctions
between research and clinical care, and
of risks and benefits of study participation,
is particularly important in office-based
research because of the special
trust patients place in their personal
physicians. This obligation was noted by
an advisory committee that investigated
thousands of radiation experiments conducted
by the federal government
between 1944 and 1974, and its importance
was illustrated by excerpts from
research subject interviews: "'[I]f you
take the time to get yourself a good doctor
and they're involved in research, they
would never steer you wrong' . . . 'Oh, I
love that man. He has kept me alive and
I obey him and I do what he tells me to
do.'"
2
The distinction between research
and clinical care may be clear in Dr.
O'Hara's mind, but he should take extra
care to explain it to patients. Mighty-med's
study, unlike Lotsapharma's,
requires informed consent to protect its
subjects and includes local IRB review,
which facilitates application of research
protections to Dr. O'Hara's local patient
population.
In sum, Lotsapharma's description
of its "study" provides Dr. O'Hara
ample ethical grounds to decline its
invitation, while Mightymed's research
appears sensibly designed, cognizant of
subject rights and welfare, and free of
inappropriate incentives.
3
1. JE Klein and AR Fleischman, "The Private
Practicing Physician-Investigator: Ethical
Implications of Clinical Research in the Office
Setting,"The Hastings Center Report July-August
2002;32(4):22-26.
2. NE Kass, J Sugarman, R Faden, and M
Schoch-Spanz, "Trust: The Fragile Foundation
of Contemporary Biomedical Research,"The
Hastings Center Report September-October
1996;26(5):25-29.
3. The Advocate Ethics Integration Council's
ethics advisory on Phase IV research can be
found on the Advocate intranet "Clinical
Resources" page.
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