Volunteers at Risk In Medical Studies

Thomas Cagle (nh-adapt@juno.com)
Sat, 8 Aug 1998 06:18:35 -0400

From: "Stephen N. Drake" 
Subject: Volunteers at Risk In Medical Studies 
Date: Fri, 7 Aug 1998 13:41:43 -0400

Hi all,

an abbreviated version of this article was posted to another list.  I
apologize for its length, but I think it's extremely important in terms
the discussion of 1) medical professional power; 2) Influence of
market/economic forces; and 3) the illusion of "safeguards" vs. the
reality of near total lack of accountability in medical research on human
subjects.  All of these have importance in the debate on legalized PID.


---------- Forwarded message ----------

Volunteers at Risk In Medical Studies
Complex Research Projects Strain System of Safeguards

By Rick Weiss
Washington Post Staff Writer
Saturday, August 1, 1998; Page A01

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
and Hispanic elementary school pupils if the children agreed to enroll in
medical study that required them to take a potentially life-threatening

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 information has begun to emerge, officials are
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
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
relating to reproductive technology or genetic predispositions.

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

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
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
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
volunteers, since the volunteers themselves rarely benefit from the

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
sake of knowledge that will benefit others," said R. Alta Charo, a
professor of law at the University of Wisconsin at Madison. "But there
deeply troubling questions about the distributive justice of how we
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
for keeping track of how many are harmed.

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,
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
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
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 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
had he been told about it. One participant, Tony LaMadrid, did not
the experiment. During a portion of the study that did not include
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
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
and LaMadrid families are suing the university.

"The current system was built for a research world that does not exist
more," said George F. Grob, an HHS deputy inspector general. "It is
brittle, strained and I think even cracked. We certainly need a better

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
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
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,
caught the attention of Sharav, director of Citizens for Responsible Care
Psychiatry and Research.

Sharav objected to several aspects of the study.

First there was the issue of using minors in a study that was
that is, a study intended to answer general scientific questions and not
benefit the children themselves. Since children cannot fully evaluate for
themselves the risks and benefits of participating in a study, some
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,
almost all instances, the use of minors in any nontherapeutic research
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
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
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
"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
as a brain hormone stimulant in children with no apparent ill effects,
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 be dangerous.

All told, the fenfluramine test posed a risk no greater than other
physical tests," concluded Danny Pine, one of the researchers in the
in a 1995 memo to the institute's IRB.

As it turns out, the institute's IRB deemed the study as posing "more
minimal risk" but approved it anyway, a decision that highlights another
ambiguity in the regulations on human research. According to federal
"more than minimal" research risks are allowed in children only if the
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
youngsters as having a "disorder."

Then there is the issue of whether it is appropriate to limit a study to
certain racial groups.

The New York researchers initially proposed conducting their study on
black and Hispanic children only. Their rationale remains unclear (and
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
only blacks and Hispanics were included. Was it a reflection of the
minority population of the neighborhood where the study was conducted,
as Walsh has suggested, or were whites systematically screened out of the

The New York researchers also offered the youngsters' parents $100 for
their children's participation, and approached the children directly,
them $25 gift certificates for toys and telling them that their
would earn money for their families. That raises another issue that has
dogged human research for decades: recruitment techniques.

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
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

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

"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

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."

Glenn's Principles

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
ethically sensitive protections for human research subjects.

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
tighter review of research, both public and private, by scientific and
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
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,
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
people with mental disabilities be made public on a regular basis, a move
that would facilitate community oversight of such research.

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
against adding new restrictions that could slow the advancement of
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,
people are militating for access to these drugs, saying, 'Who are you to
protecting me against my own choices?' " said professor Charo.

Unfortunately, Charo and others said, while some trials are indeed
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 and the public eventually will have to
to what extent the government should help people distinguish between
those kinds of research, and to what extent people will have to heed a
version of an old aphorism: "Volunteer beware."


At the core of the system that protects people participating in research
the "common rule." Seventeen federal agencies subscribe to that rule,
which, among other things, requires that human studies conducted by those
agencies be reviewed in advance by an independent board, and all
volunteers be fully informed of any risks.

Universities and other institutions funded by any of those agencies must
also adhere to those protections, as must private enterprises developing
products for which Food and Drug Administration approval will be sought.

But that leaves a lot of human research unregulated, including all
research funded by agencies that are not a party to the common rule,
including, for example, the Labor Department and the Nuclear Regulatory
Commission. In addition, all privately funded research not heading for
FDA is excluded, including the vast majority of human studies conducted
at fertility clinics, weight-loss clinics, psychotherapists' offices,
testing companies and plastic surgeons' offices.

In 1994, President Clinton ordered all federal agencies to come into
compliance with the common rule or halt their human research. Four years
later, however, no additional agencies have signed on to the rule. And
according to one knowledgeable federal official, there is "no evidence
any department or agency has suspended a single activity."

Bureaucratic complications make it nearly impossible for the 17 agencies
that subscribe to the common rule to close the loopholes that remain in
rule. Federal regulations require that even minor changes must be
independently considered and approved by all 17 agencies, a cumbersome
process that can take years under the best of circumstances.

Critics of the system have called for two major changes. One is to move
the Office for Protection From Research Risks (OPRR), which oversees
federally funded research, out of its low-level position in the National
Institutes of Health to a higher-ranking position, perhaps in the office
of the
secretary of health and human services, where it might gain the clout it
needs to fulfill its wide responsibility to protect U.S. human research

experts outside the office. The OPRR currently has 70 complaints on its
investigative agenda but only one full-time investigator.

The second major change advocated by some is to enact broad legislation
that would extend the federal protections of the common rule to all
research volunteers, including people in privately financed studies.

                  ABOUT THIS SERIES

Biomedical research is proceeding at breathtaking speed.

Geneticists are gaining insights into how genes work. Biologists are
unmasking the mysteries of how a tiny clump of cells develops into a
formed human. Immunologists are deciphering the complexities of the
body's defense systems.

The research is yielding many potential benefits. Doctors can identify
people at risk for genetic diseases and fashion strategies to save their
Reproductive biologists can help infertile couples have children.
Researchers can engineer animals with organs that may be transplanted
into humans.

But as science speeds ahead, it often pushes the edges of society's
eadiness to cope with its consequences. Increasingly, research creates
possibilities before the accompanying ethical, social and legal
have been resolved. In a series of occasional articles, The Washington
examines whether people are adequately protected when they volunteer
for medical research.

The previous installments, which were published Oct. 12 and Nov. 24,
1997, and Feb. 8-9, March 22 and June 7, 1998, examined the use of=20
gene therapy for "cosmetic purposes," the possibility of making genetic
changes before conception, aggressive measures for harvesting organs for
transplantation, fertility research and its social implications, and
engineering mice for research.

                  SUBJECTS OF SCRUTINY

Federal regulations governing medical research involving human beings
apply only to studies funded by the 17 federal agencies that adhere to
so-called common rule, and to private enterprises developing drugs or
medical devices for which Food and Drug Administration approval will be

funded by:

* Colleges and universities not receiving federal research funds

* In vitro fertilization clinics

* Weight-loss or diet clinics

* Physician, dentist and psychotherapist offices

* Corporate and industrial health, safety and fitness programs

* Developers of genetic tests

* Department of Labor

* Nuclear Regulatory Commission

Some research organizations are being criticized for overstating the
and understating the risks in their solicitations for human test
Above are two advertisements on a Philadelphia subway car that were
cited in a recent Department of Health and Human Services report.  (Not
Included on Web Version of Article)

                  SOURCE: Health and Human Services Department

                          Copyright 1998 The Washington Post Company