AIDS TREATMENT NEWS Issue #217, February 17, 1995
One of the functions of a publication such as AIDS TREATMENT
NEWS is to provide information about clinical studies of new
treatments. Often those of us who report on AIDS trials hear
that potentially important studies are having trouble
enrolling the number of volunteers needed.
The problem is quite common. Ronald Mitsuyasu, M.D., director
of UCLA's Center for Clinical AIDS Research and Education, a
major southern California clinical trial site, comments that
"the majority of our trials take a lot longer than anybody
expected to enroll. My guess is that this is what's happening
across the country." In fact, Dr. Mitsuyasu says, "very few"
UCLA AIDS trials enroll on schedule.
This is a significant problem. Collection of needed data can
be greatly delayed. Worse, if trials are underenrolled, or if
the factors that cause people not to enroll also lead large
numbers of volunteers to drop out or "cheat," either by lying
to get into the study or by not following the trial regimen,
the result could be data that is of little or no value, even
though produced at great expense.
Obstacles to enrollment in AIDS trials generally fall into
one of two broad areas: The publicity or outreach efforts
used to recruit prospective volunteers, and the design of the
Publicity and Outreach
The news releases, flyers and other materials designed to
publicize trials vary widely in content and quality. Some
that we have seen are excellent, giving a clear description
of the treatment being studied, what is known about it thus
far and the nature of the research being announced, in
language that nonscientists (which includes most of the
writers and editors likely to make use of this material) can
understand. Others are problematic at best, omitting key
information or so mired in jargon as to be incomprehensible
to most lay people.
Mark Bowers, who until recently recruited potential trial
participants as Clinical Outreach Coordinator at HIV Care,
the research division of St. Francis Memorial Hospital in San
Francisco, puts some of the blame on what he calls the drug
companies' "proprietary, closed-mouthed attitude" about new
compounds. "On the one hand they want to recruit their study.
On the other hand, they do not want anybody else to know they
are doing it, and they do not want the slightest amount of
information to be leaked out to the public." This reluctance
to release data developed in-house on a prospective drug,
Bowers says, at times made it difficult for him to give
potential volunteers the information they needed to feel safe
in the study.
Another apparent obstacle to publicizing trials is the lack
of clear guidance from the FDA on what publicity materials
should or should not say, which may lead some trial sponsors
to err on the side of caution by not saying much at all.
Jennifer Fernandez, Product Communication Manager for Immune
Response Corporation, the company developing the Salk
Immunogen therapeutic HIV vaccine, calls the FDA's rules "a
real gray zone."
The formal FDA regulations which lay out procedures for
informed consent, the responsibilities of Institutional
Review Boards, etc., say nothing specific about publicity for
trials. The only written rules the Agency has, according to
spokesman Arthur Whitmore, is in the form of a one and one-
quarter page "guidance document"--a notch below a formal
regulation in the bureaucratic pecking order--titled,
"Advertising for Study Subjects."
The document deals specifically with advertising, making no
mention of other forms of publicity such as news releases.
The general principles contained apply across-the-board,
Whitmore says, but in conversations with him and with Richard
Klein of the FDA's Office of AIDS, it appears that relatively
little thought has been given to the news releases that
treatment publications, the gay press, and mainstream media
outlets often rely on for basic information about new
The basics are relatively straightforward: Publicity
materials should be reviewed by an Institutional Review
Board, which should treat them as an extension of the
informed consent process. They should not be inaccurate,
misleading, or claim that an experimental drug has been shown
safe or effective.
The document then goes on to state, "Generally, the FDA
believes that any advertisement to recruit subjects should be
"1) The name and address of the clinical investigator;
"2) The purpose of the research and, in summary form, the
eligibility criteria that will be used to admit subjects
into the study;
"3) A straightforward and truthful description of the
benefits (e.g., payments or free treatment) to the
subject from participation in the study; and
"4) The location of the research and the person to contact
for further information."
The language is quite vague: How much detail, for example, is
appropriate in a description of "the purpose of the
research"? A great deal of information which might be of
interest is not included, such as information about the study
drug, its believed mechanism of action and the results of
prior research. It does not seem unreasonable to speculate
that fear of putting too much detail into an "advertisement"
may account for the sketchiness of some press releases
"I think for the most part people in the Agency do not
interpret this [document] word-for-word or really narrowly,"
Klein explains, emphasizing that the idea is to make sure
that information is accurate and that no one is misled into
thinking they are taking a drug that has been proven
effective when it is still experimental. Unfortunately, the
Agency has not put this sentiment in writing.
Once publicity materials have been developed, getting the
word out can become a problem, particularly when there is
little budget for paid advertisements. Treatment publications
reach one segment of potential volunteers, as does the gay
press, which sometimes runs announcements of studies. But
many potential candidates for HIV/AIDS trials are not reached
by these publications, and information about studies that are
recruiting rarely finds its way into mainstream media outlets
which might reach a broader audience.
Women, People of Color, and Other "Underserved Populations"
For years activists have complained about the
underrepresentation in AIDS clinical trials of women,
injection drug users, and people of color, despite the fact
that these groups represent a large and growing proportion of
AIDS cases. These complaints have often centered around the
worry that drugs are not being tested on a population that is
representative of those who will actually use them, and that
potentially important information about a given drug's
activity and toxicities may be left undiscovered. And in
addition to that consideration, it appears that a substantial
pool of potential volunteers is being left largely untapped.
Jeannett Ickovics, Ph.D., of the Yale University School of
Medicine, has studied both participants and non-participants
in AIDS trials at the Nathan Smith Clinic, the location of
Yale's AIDS Clinical Trials Unit. Her findings, the bulk of
which have not yet been published, raise a number of issues.
Of patients in the clinic who were not enrolled in a trial,
35.3% had not heard of clinical trials at all, and 55.6% did
not know that the clinic had an ACTU [AIDS Clinical Trial
Unit]. But 56.9% said they would be willing to participate in
a study if asked. In a clinic where much of the recruitment
for trials happens through individual physicians telling
individual patients about studies which may be of interest,
72.5% had not yet been asked. Latinos, and also current or
recent injection drug users, were least likely to have been
asked to participate.
Significantly, Ickovics' study of those who were trial
participants suggests that common stereotypes branding
certain groups as being unreliable study participants are
false. "Neither sex, race nor history of injection drug use
were associated with non-adherence to medication regimen,"
she writes. Even so, "Injection drug users are often excluded
from clinical trials by inclusion criteria that explicitly
(e.g. no active drug users) or implicitly (e.g. high
standards for liver function tests) eliminate them from
Jeff Getty, a treatment activist who volunteers at the Center
for AIDS Services in Oakland, California, in addition to
being a member of ACT UP/Golden Gate, says that clinical
investigators frequently are unwilling to accommodate the
needs of the people with whom he works, many of whom are
women, people of color, or people with a history of injection
Before many of these individuals can even think about joining
a study, Getty explains, "they have a lot of pressing needs
that need to be met in terms of housing, shelter, paying
their bills. They need help with things like transportation
and child care, and even a small reimbursement. If you think
rich peoples' time is money, look at poor people."
For people who are barely making ends meet, the cost of
transportation across the bay to San Francisco, where the
majority of nearby studies occur, and of arranging child care
for the time involved, can be an insurmountable obstacle.
Trial sponsors, Getty complains, have only rarely made an
effort to accommodate such needs--and never do so for popular
studies of treatments perceived as "hot" in the community.
"There is an unspoken prejudice that's quietly there, keeping
women, the poor and IDUs out of these studies," Getty argues.
"There are thousands of people in the East Bay who could be
in these studies, but they are not."
Although there has been some progress in increasing the
numbers of women and minorities in trials, and even though
the FDA is on record as encouraging such inclusion, there is
clearly more work to be done in this area.
Study Design Issues
Of course, all the publicity, outreach and accommodation of
financial and other barriers in the world will not attract
people to a trial whose design is inherently unappealing to
patients or whose inclusion/exclusion criteria shut out too
many potential volunteers. This is another longstanding
complaint of the activist community, one with which many
researchers at least partly agree.
Sometimes a study's design keeps out the very people
researchers need to recruit. One of the clearest examples of
this occurred about a year and a half ago, in what eventually
became an important study of recombinant human growth hormone
as a treatment for wasting syndrome. After nearly a year of
recruitment, the study was enrolling at a painfully slow
pace. The problem turned out to be the exclusion criteria,
which among other things barred anyone taking either d4T or
3TC, both drugs that were not yet approved but were available
to many patients via either large-scale clinical trials or
expanded access. After activists successfully lobbied to have
the exclusions dropped, the enrollment problem disappeared.
The motivation for such exclusions is usually a desire for
"clean" data, uncluttered by the "noise" which might be
produced by other drugs--particularly unapproved ones, about
which less may be known. But in this case the trial's
designers had failed to consider the fact that wasting is
generally a manifestation of late-stage disease, and people
with wasting were likely to have already gone through all of
the approved drugs and moved on to the newer ones. They were
barring the very patients who most needed and wanted the
treatment they were studying.
Greg Dubs, Ph.D., has seen the issue of trial design from two
angles: As Project Director of the recently-completed
Stanford NAC trial, and as a person with HIV who has himself
tried unsuccessfully to get into studies as a volunteer. The
culprit in his case, he argues, has been needlessly
restrictive entry criteria. Dubs says his platelet count,
which varies between 72,000 and 90,000, has disqualified him
from "almost 90% of the studies, because they always ask for
platelets over 100,000... And yet my platelet count has
essentially no clinical significance whatsoever. It has been
stable for five years."
Sometimes, he argues, those criteria exist for no good
reason. "I've sat in so many protocol discussions where I
questioned a criterion, and the reason that criterion had
been put in place was not through any rational process, but
because they had taken it from another protocol." He is
particularly critical of those antiretroviral studies--still
fairly common--that insist on patients with relatively low
CD4 counts who either have never taken antiretrovirals or who
have only very limited experience with them. Such an
approach, he argues, is absurd in a city like San Francisco
where--except for those who have chosen not to take
antiretrovirals at all and who thus would have no interest in
such a study--the vast majority of HIV patients with low CD4
counts have been on AZT or its cousins for some time.
By putting out exclusion criteria that few can meet, Dubs
says, "all you are doing is finding out who can lie well.
They never study how many people lie to get into their
Dr. Mitsuyasu agrees that inclusion criteria are frequently
too narrow. "I'm not going to try to defend that policy,
because in most cases I can't," he comments. "The reason for
doing it is to make the drugs look good... You are going to
see the biggest change in naive patients." Another unhappy
result, he adds, is that potential volunteers get discouraged
if they repeatedly fail to meet the entry criteria for
studies they would like to participate in. "Sometimes they
don't come back," he says.
A related issue is the continuing prevalence of study designs
that in the view of many do not fit into the real-world needs
of patients. As the consensus grows that combinations of
antiviral agents--most likely with periodic changes to ward
of viral resistance--are the most effective treatment
strategy, long-term monotherapy trials become less and less
Bowers takes the argument a step further. "It will soon be
perceived by a sizable segment of the activist community...
that denying anybody the opportunity for combination therapy
from the get-go is unethical. The best evidence that we have
today shows that combination therapy started at the earliest
possible moment provides the longest and most reasonable
benefit, and it is unethical to deny anyone that, just as it
is unethical to do long-term placebo-controlled studies."
Bowers argues that study designs must evolve more rapidly in
order both to attract volunteers and to produce results that
reflect the way doctors and patients treat HIV/AIDS in the
real world--making more allowances for combinations of drugs
and pragmatic adjustments in treatment over time.
In a recent position paper, Project Inform founder Martin
Delaney argued, "we should consider going to war against
anyone planning to run long-term studies which include the
possibility of randomization to a monotherapy arm, unless
there are clear provisions to move such unlucky patients to
better therapy at the first sign of returning virus levels."
Such an attitude, he added, probably means confrontation with
common drug-development strategies and with the FDA, "since
meeting Agency requirements is the principal reason companies
are doing things that way."
The FDA's Klein insists that "the Agency encourages, to the
extent that they can, combination therapy--they are working
with the ICC [the Intercompany Collaboration for AIDS Drug
Development, which is testing drug combinations]--but it's
not for the Agency to dictate how people do research."
Mitsuyasu agrees that the Agency is becoming "more
responsive," but says it still has trouble keeping up with
the changing science in the field.
Perhaps most disturbingly, many, including Dubs and
Mitsuyasu, say they detect a growing malaise among PWAs when
it comes to volunteering for trials. "Even before we screen
them we are having trouble getting people to call," Mitsuyasu
notes. "Patients are almost burnt out, and maybe somewhat
pessimistic about what trials can do for them."