Research Volunteers Unwittingly at Risk
Last in a series of occasional articles
By Rick Weiss
Washington Post Staff Writer
Saturday, Aug. 1, 1998; Page A1
It seemed a stunning example of medical research run amok: Physicians in New York offered
to give Toys R Us gift certificates to 36 healthy black and Hispanic elementary school
pupils if the children agreed to enroll in a medical study that required them to take a
potentially life-threatening drug.
The three-year study, recently revealed by a patient advocacy group, brought back memories
of the infamous Tuskegee experiments that came to light in the 1970s, in which doctors
withheld syphilis treatments from black men so they could observe the disease's
progression. Congress quickly convened two hearings, and federal officials launched an
Now, as additional facts have begun to emerge, officials are realizing that the facts
involved in the New York study are much more nuanced and complicated than was initially
thought. It's no longer clear whether the study endangered the children or was racist.
Indeed, more than anything, the controversy highlights the surprisingly thin line that can
separate a justifiable human experiment from a research abuse. And it shows that important
issues relating to the ethics of human research remain unresolved, even as U.S. medical
research is poised to expand at an unprecedented rate.
Medical research is changing dramatically. Modest studies aimed at answering
straightforward questions are giving way to large, complex research projects freighted
with social and ethical baggage, such as those relating to reproductive technology or
Public perceptions are shifting too. "Guinea pig" was once a pejorative term,
but many people with AIDS, cancer and other serious diseases are now demanding access to
experimental drugs as their best hope for survival.
Those scientific and social changes have led to a sharp increase in the number of people
participating in experiments, and have strained the nation's system of protections for
research volunteers. With Congress now preparing to double the budget of the National
Institutes of Health in the next five years, many legislators, ethicists and patient
advocates believe it is time to upgrade that fragile system.
"It's a very special privilege to use human beings in research," said Vera
Hassner Sharav, the activist who first rang alarms about the New York study three months
ago. "It must not be handled cavalierly."
Redefining the rules will not be easy, however, because human experimentation raises
profound moral questions, the answers to which have remained elusive even to philosophers
and ethicists who have pondered them for years:
When, if ever, is it appropriate to conduct research on minors or the mentally
incompetent, who are by definition unable to give legal consent?
If such research is inappropriate, then how can scientists develop drugs and therapies for
these needy and often underserved patient groups?
Is there anything wrong with offering cash or other incentives to research volunteers,
since the volunteers themselves rarely benefit from the research?
Or might incentives seduce poor or medically desperate people into taking unwise risks,
and perhaps foster the creation of an underclass of professional human guinea pigs?
"Research most often requires that some people get exposed to risk for the sake of
knowledge that will benefit others," said R. Alta Charo, a professor of law at the
University of Wisconsin at Madison. "But there are deeply troubling questions about
the distributive justice of how we decide who will bear that risk and who will not."
Evidence of Abuses
No one knows how many people participate in human research in this country. There is no
central repository for such information, and no system for keeping track of how many are
But there is indirect evidence that abuses are taking place.
In June, a Department of Health and Human Services report concluded that the federal
system for protecting human research subjects was breaking down. The report found that
institutional review boards (IRBs), which judge the scientific and ethical merit of
proposed human studies, are overburdened with work, staffed by insufficiently trained
people and subject to conflicts of interest.
That report did not cite specific improprieties, but in 1995 the HHS Office of the
Inspector General reviewed human tests of four experimental medical devices. In three out
of four cases, physicians tested the devices in more people than they were supposed to or
continued the experiments longer than they had permission to.
Moreover, in half the cases, volunteers were not adequately informed of the risks. In some
cases, people were asked to sign consent forms only after the experimental devices had
been surgically implanted inside them.
Additional evidence of trouble arose last year as several people testified before the
National Bioethics Advisory Commission about alleged abuses they or their family members
had endured in psychiatric research studies.
Robert and Gloria Aller of Los Angeles described a University of California study in which
their schizophrenic son, Gregory, had enrolled. Gregory had been doing well, earning a 3.8
grade point average in college and working 15 hours a week. But the study, which started
in 1989, required him to discontinue his medication. Deprived of his medicine, he became
confused and violent and lost his ability to concentrate. Years later, Robert Aller said,
Gregory still has not fully recovered.
Only after a federal investigation was launched did the Allers learn that more than 90
percent of previous subjects in that experiment had also relapsed, a fact they believe
would have dissuaded Gregory from enrolling, had he been told about it. One participant,
Tony LaMadrid, did not survive the experiment. During a portion of the study that did not
include regular doctor visits, he jumped to his death from the roof of UCLA's engineering
"They claim that care in a research setting is better than the deficient care you'd
get in the community," Aller said in an interview. "But [LaMadrid] was merely
seen as a source of data."
A report by the federal Office for Protection From Research Risks (OPRR) criticized that
study's consent forms for failing to properly warn participants that the research was
likely to trigger a relapse. Now the Aller and LaMadrid families are suing the university.
"The current system was built for a research world that does not exist any
more," said George F. Grob, an HHS deputy inspector general. "It is brittle,
strained and I think even cracked. We certainly need a better one."
Children as Subjects
The New York case, which involved minority children age 6 to 10, highlights many of the
issues that ethicists and regulators will face as they consider how to fix that system.
The research, which ended in 1995, was designed to study the biology and sociology of
criminal behavior. Physicians at the New York State Psychiatric Institute and three other
hospitals recruited the younger brothers of adolescents who had been arrested for various
crimes. The goal was to identify which younger brothers might be at increased risk for
trouble themselves, and intervene with counseling or other methods before it was too late.
As part of the study, researchers gave each younger sibling a dose of a drug called
fenfluramine to help measure levels of a brain hormone implicated in antisocial behavior.
When the work was published last year, it caught the attention of Sharav, director of
Citizens for Responsible Care in Psychiatry and Research.
Sharav objected to several aspects of the study.
First there was the issue of using minors in a study that was nontherapeutic; that is, a
study intended to answer general scientific questions and not to benefit the children
themselves. Since children cannot fully evaluate for themselves the risks and benefits of
participating in a study, some argue they should never be subjected to a research risk if
they do not stand to personally benefit. Others, however, argue that the only way to
develop new treatments for children is to study them directly.
Federal regulations try to address those conflicting views by precluding, in almost all
instances, the use of minors in any nontherapeutic research that poses a "more than
minimal risk." That sounds reasonable, Sharav said, except that "nobody has
defined 'risk' or 'minimal' or 'more than minimal.'" And as the New York case shows,
it is not obvious how to distinguish between those levels of risk.
For example, Fenfluramine was never approved for use in minors. And although it was
approved for use as a diet drug in adults, it was pulled off the market by the Food and
Drug Administration in September after it caused several deaths. In addition, as part of
the fenfluramine test, the children had to fast for 18 hours and had a catheter placed in
a vein from which multiple blood samples were drawn over several hours, a procedure that
left some feeling nauseous and headachy.
Those details alone have convinced some people that such a test is unconscionable in
children. The fact that it was approved by an IRB, said Rep. Christopher Shays (R-Conn.)
at a hearing last month, is evidence that "the current system of bioethical review
has failed miserably."
Not so, replied B. Timothy Walsh, co-chair of the Psychiatric Institute's institutional
review board. Scientists have for many years used fenfluramine as a brain hormone
stimulant in children with no apparent ill effects, Walsh told Congress. The drug's
connection to heart damage was unknown when the experiments were conducted. And in any
case, only a single small dose was used in the study, as compared with the much higher
doses and longer periods of use that, when combined with another drug, have been shown to
All told, the fenfluramine test posed a risk no greater than other "routine physical
tests," concluded Danny Pine, one of the researchers involved in the study, in a 1995
memo to the institute's IRB.
As it turns out, the institute's IRB deemed the study as posing "more than minimal
risk" but approved it anyway, a decision that highlights another ambiguity in the
regulations on human research. According to federal rules, "more than minimal"
research risks are allowed in children only if the study promises to yield useful
information about the children's "disorder or condition" (and even then the
research must pose no more than a "minor" risk above minimal risk).
But what disorder or condition afflicted these children? The researchers noted in their
study proposal that the younger siblings of juvenile delinquents have increased odds of
eventually getting into trouble themselves. But it would be a stretch, critics said, to
consider these young boys as having a "disorder."
Then there is the issue of whether it is appropriate to limit a study to certain racial
The New York researchers initially proposed conducting their study on black and Hispanic
children only. Their rationale remains unclear (and they have refused to speak to
reporters), but scientists often try to work with as homogeneous a population as possible,
lest racial or other variables confound their results.
The IRB rejected that aspect of the study design and demanded that whites be eligible as
well. Now investigators want to know why, in the end, only blacks and Hispanics were
included. Was it a reflection of the mostly minority population of the neighborhood where
the study was conducted, as Walsh has suggested, or were whites systematically screened
out of the study?
The New York researchers also offered the youngsters' parents $100 for their children's
participation, and approached the children directly, offering them $25 gift certificates
for toys and telling them that their participation would earn money for their families.
That raises another issue that has dogged human research for decades: recruitment
Cash payments and other incentives are commonplace in medical research. But they are
offered as compensation for a person's time, not as a fee for accepting risk, said Gary B.
Ellis, head of the OPRR, and amounts are supposed to be modest enough so as not to tempt
people to waive their better judgment.
The line between acceptable and exorbitant compensation is subjective, but the issue goes
beyond the question of "How much?" Subtle issues of power must also be
considered. When the youngsters were told that their families would be given cash, for
example, might some of them have worried that their parents, mostly poor, would be angry
if they refused to participate?
Moreover, the parents were first contacted by researchers who had gotten their names
through the judicial system that had arraigned their older children. Might some parents
have worried that a decision not to participate in the study might adversely affect their
children's upcoming court cases?
The June HHS report cites several examples of recruitment ads that are decidedly lopsided
in their descriptions of the risks and benefits of participation in research. One
newspaper ad read: "Speed or Cocaine? Need help getting clean? Free Treatment &
Medication! Repeat callers welcome!!! Get Paid $$$." As usual for such ads, there is
no mention of risk.
"The kind of ads we've seen present a real problem," said Mark Yessian, a
regional HHS inspector general. "When you see an emphasis on cash payments and
benefits, and little or no mention of risks, that's a real concern."
Of course, ads are just the first round of recruitment; if the system is working well,
then researchers will explain the risks in proper detail when a volunteer arrives. But as
Gregory Aller and others learned, full and fair disclosure is not always provided.
"This is research. It is not standard treatment," Yessian said. "It does
involve risk and one should fully recognize that from the start."
The New York study is now under investigation by the OPRR, and a final judgment is not
expected until fall. But the lack of easy answers to the questions raised by the case
suggest it's going to be difficult to draft new, ethically sensitive protections for human
The National Bioethics Advisory Commission has spent much of the past year analyzing the
various ethical implications of human research. It has called for a more thorough informed
consent process for all volunteers and tighter review of research, both public and
private, by scientific and ethical review boards. Those are also the central principles of
a human subjects protection bill sponsored by Sen. John Glenn (D-Ohio) that has languished
since its introduction last year.
The commission has also expressed concern about the lack of explicit protections for the
mentally ill, who frequently are subjected to "wash out" studies, in which
helpful medicines are withdrawn, and "provocation" studies, in which symptoms
are intentionally exacerbated for study. A commission report, due this fall and presaged
already in a public draft, calls for added protections for this vulnerable population.
Meanwhile, a bill introduced in June by Rep. Edolphus Towns (D-N.Y.) would require that
all biomedical or behavioral studies involving minors or people with mental disabilities
be made public on a regular basis, a move that would facilitate community oversight of
But it remains to be seen whether such steps will pass muster with the biomedical research
lobby, or even with some patients. At a recent congressional hearing, the Association of
American Medical Colleges and the Pharmaceutical Researchers and Manufacturers of America
argued that the nation's system of research protections is working well. They cautioned
against adding new restrictions that could slow the advancement of life-saving research.
Many patients too are wary of government efforts to restrict access to medical research.
"We have a society that tends to view everything that's new as better, and people are
militating for access to these drugs, saying, 'Who are you to be protecting me against my
own choices?'" said professor Charo.
Unfortunately, Charo and others said, while some trials are indeed testing tomorrow's
miracle drugs, others are testing useless or even harmful compounds, or are so poorly
designed that they won't yield any useful information at all. Lawmakers a and the public
eventually will have to decide to what extent the government should help people
distinguish between those kinds of research, and to what extent people will have to heed a
new version of an old aphorism: "Volunteer beware."
Copyright 1998 The Washington Post Company
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