[Pharm-policy] IL-2 trials -- $43 million will be most expensive trial for AIDS treatment ever sponsored by NIAID

[James Love]

I am grateful to MP for a pointer to this article, which I am posting
as a fair use.   Jamie

Volume 285, Number 5436 Issue of 24 Sep 1999, pp. 2039 - 2042 
(c) 1999 by The American Association for the Advancement of Science. 


AIDS THERAPY:
Ambitious Clinical Trial Stirs Debate
Jon Cohen

The National Institute of Allergy and Infectious Diseases (NIAID) last
week
decided to fund what will likely be the largest and most expensive trial
of
an AIDS treatment the institute has ever backed. During the next 5
years,
the $43 million study will follow 4000 HIV-infected people who are
already
taking anti-HIV drugs to see whether adding an immune-system messenger
called interleukin-2 (IL-2) can help prevent disease and death. The
study,
which went through a stringent but unusual review process because NIAID
director Anthony Fauci holds a patent on the treatment, will involve 210
sites in 18 countries, creating an enormous new clinical trials network
that
will include some of the world's leading AIDS clinicians. "It's
tremendously
ambitious," acknowledges Jack Killen, head of NIAID's Division of AIDS.
"But
this is about as good a shot as we're going to get at answering a very
important question."

Whether the so-called Esprit trial is likely to yield meaningful results
is,
however, being fiercely debated within the AIDS research community. Some
researchers believe its flexible design and relatively healthy subjects
may
blur any results. And numerous other logistical, procedural, and ethical
questions have also dogged this trial since it was first conceived 3
years
ago, including whether the costly study is needed when smaller IL-2
trials
are already planned in sicker subjects.

Small-scale studies have shown that genetically engineered IL-2
significantly boosts levels of CD4 cells in HIV-infected people. (CD4s
are
the main white blood cells that HIV selectively destroys.) "We have seen
changes in CD4 counts, but we don't know what they mean clinically,"
explains NIAID's clinical director Clifford Lane, who pioneered this
treatment strategy and shares the patent with Fauci and NIAID's Joseph
Kovacs. (The patent is assigned to the government, and Chiron, the maker
of
engineered IL-2, has a license; the researchers are entitled to a
maximum of
$150,000 of any payments each year, which Fauci donates to charity.)
Specifically, none of the trials have yet shown that the CD4 increases
result in longer, healthier lives, and the treatment does not seem to
decrease the amount of HIV in a person's bloodstream.

The trial aims to mimic the diverse ways IL-2 would be used in the real
world. In the first 6 months, 2000 people already taking any combination
of
anti-HIV drugs will give themselves injections of IL-2 for 5 days every
8
weeks. After those three cycles, physicians will use their discretion to
determine the frequency of subsequent cycles of IL-2 treatment, which
can
cause flulike symptoms. Another 2000 people who are taking only anti-HIV
drugs will serve as the control group. "This will give some pretty clear
information," asserts Lane.

Others aren't so sure--including the peer-review group that ultimately
gave
the trial a thumbs-up. "A lot of people are skeptical about whether it
will
be possible at the end of a large trial like this to sort out the cause
and
effect when people cycle through different treatments," acknowledges
Killen.
And the link may be further blurred because Esprit will recruit people
who
have suffered relatively modest immune damage from HIV and thus are more
likely to respond to the immune booster; to be eligible, HIV-infected
people
must have at least 300 CD4 cells per millimeter of blood at the trial's
start. (The normal range is 600 to 1200.) As a result, it may take
longer
than 5 years to see enough AIDS-related disease and death to determine
conclusively whether IL-2 helps. "You could be holding your breath a
long
time," says Robert Schooley of the University of Colorado Health
Sciences
Center in Denver, who heads the AIDS Clinical Trials Group (ACTG), an
NIAID-supported network that conducts most trials of AIDS drugs.

The fact that ACTG will not be running this trial is another point of
contention. James Neaton of the University of Minnesota, Minneapolis, a
biostatistician who is Esprit's principal investigator, says he couldn't
interest ACTG. "People I worked with [in the ACTG] wanted to
participate,
but they couldn't get approval from the executive committee," says
Neaton.
Schooley explains that not only would the expense overwhelm the ACTG's
budget, but ACTG is already conducting a smaller scale trial of IL-2 in
sicker patients. "Our feeling is it really offers more to people with
advanced disease," he says. (Indeed, Chiron last month launched a large
efficacy trial of the treatment in people with 50 to 300 CD4s.) Schooley
also questions whether patients with relatively high CD4 counts will
choose
this toxic and expensive drug. "If you have 700 CD4s, you're going to do
well for a long time," says Schooley.

Neaton also considered another NIAID-sponsored clinical trials network,
the
Community Programs for Clinical Research on AIDS (CPCRA), but it did not
have enough sites to recruit the needed number of patients. So, on
advice
from NIAID, he turned to a mechanism that is rarely used to fund large
clinical trials: He submitted an investigator-initiated, "R01" grant.

To help avoid the perceived conflict-of-interest issues raised by
Fauci's
patent, the ad hoc "study section" of peers set up to evaluate the
proposal
was convened by the National Cancer Institute, not NIAID. "I can tell
you
for a fact that Tony had no influence whatsoever on the process of
review or
the decision about the funding of this," says Killen. Lane, who did help
design the trial, says National Institutes of Health lawyers gave him a
waiver for that purpose.

Unlike ACTG and CPCRA, study sections evaluate proposals behind closed
doors. But interviews with members of the study section and documents
provided by Neaton suggest that it received a rigorous review. When the
study section first evaluated the proposal in June 1998, it gave it a
score
of 322, which put it in the unfundable 59.3 percentile. Among the many
concerns listed by the study section was "whether the study as currently
designed will result in interpretable data." Another sensitive topic was
that some testing would be done in poor countries that may not be able
to
afford IL-2 if it is found to work: Three treatment cycles cost at least
$5000.

The same study section considered a revised proposal 8 months later, and
although it still noted "several weaknesses," it deemed the trial design
"significantly improved." This time around, it earned a priority score
of
178, placing it in the 18.1 percentile, an excellent ranking. On 16
September, NIAID formally announced that it would fund the trial.
Leading
clinicians in the United States (including those with the CPCRA),
Canada,
Europe, Australia, Greece, Israel, Thailand, and Argentina will
participate.

Even if the treatment itself doesn't pan out, Neaton thinks the trial
could
have an important benefit: to show how "large, simple trials" that
mirror
real-world situations can answer tough questions. "I'm hoping to make
this a
model for how other research is done," he says.