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Author Topic: Randomization Roulette: Access to life saving treatments for salvage patients.  (Read 2238 times)

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Offline Smoothstone

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From POZ Magazine

Randomization Roulette: Are Current Studies Fair for Those With No Options?
August 21, 2007
By Kenyon Farrow

Advances in HIV treatment have helped save millions of lives, but the pace of
the pipeline may be too slow for those who have run out of antiretroviral (ARV)
options. The best hope for these “salvage” patients with multiple-drug-resistant
HIV is access to experimental agents through clinical trials, but this route
doesn’t come with any guarantees. First there’s the randomization roulette—the
possibility that they’ll be assigned to the control group and won’t receive the
new drug. Then there’s the risk of not having other active ARVs to use in the
study, resulting in rapid resistance to the new drug and little hope of
long-term success.
While these trials are helping to solidify effective options for tomorrow’s
treatment-experienced patients, what can be done for today’s HIV-positive people
at the end of their treatment rope and turning to salvage studies for help? A
small group headed by Michael Lederman, MD, of Case Western Reserve University
in Cleveland thinks it has the answer—but one that comes with controversy.

In an opinion piece published in the July 31 issue AIDS, Dr. Lederman and his
fellow authors—including Veronica Miller, PhD, of the Forum for Collaborative
HIV Research; Ian Weller, MD, of the University College London; and Steven
Deeks, MD, of the University of California, San Francisco—propose wiping out the
control arm in studies involving salvage patients. These clinical trials, they
suggest, should be “single arm,” in which everyone enrolled gets the
experimental ARV along with at least one other active drug to help keep
resistance at bay.

But how would these studies work, if their primary goal is to show how well a
new drug works in comparison to approved options? To prove efficacy, Dr.
Lederman and his peers suggest turning to the results of clinical trials of the
other agents that will be used by patients during the single-arm study. The data
from these clinical trials, which involved patients with varying degrees of drug
resistance, could be used to predict what would happen to viral loads and CD4
cell counts without the addition of the experimental drug. Once the new ARV is
added, the researchers could look at the net difference in efficacy parameters,
such as a greater percentage of patients with undetectable viral loads after six
months of treatment.

“This would permit us to evaluate the utility of the new drug in the context of
what has been seen in the past with other new drugs used in combination,” says
Dr. Lederman.

While this approach would help guarantee access to a promising new agent, there
is also the issue of what is known as “sequential monotherapy.” During the early
years of HIV treatment, patients were often switched from one drug, such as
Retrovir (zidovudine), to another, such as Videx (didanosine), resulting in
quick and extensive drug resistance.

The same danger is present in current salvage studies, in which many patients
add a promising experimental drug to a regimen that his or her virus is already
highly resistant to. In effect, the new agent is being used like
monotherapy—without other effective drugs to prevent or slow the emergence of
virus that is resistant to the novel compound.

“That’s what’s been the problem, and that’s what we’re trying to avoid in the
future,” says Nelson Vergel, a treatment activist with multiple-drug-resistant
HIV infection who has been working for years to help improve outcomes for
salvage patients in clinical trials. “We don’t want anyone to be exposed to
sequential monotherapy.”
Vergel knows from personal experience the potential risk of studies that offer
patients an experimental agent without ensuring that it is combined with at
least one active drug. He is a participant in a clinical trial of Merck’s
integrase inhibitor Isentress (raltegravir) for highly treatment-experienced
patients. After being randomized to the Isentress group, not the control arm,
his viral load dropped from 60,000 to under 50 by the fifth week of treatment.
By week 24, however, his viral load had rebounded to 20,000.

It turned out that Vergel’s HIV was resistant to all of the drugs he was using
in combination with Isentress. “There are a lot of people walking around like
me, with integrase resistance because of the studies that expose people to
sequential monotherapy,” he says.

To help protect against the dangers of sequential monotherapy, Dr. Lederman’s
group is also proposing studies requiring that the experimental drug be combined
with at least one other ARV that a patient’s virus is fully sensitive to,
determined by using drug-resistance testing at the start of the study.

Unfortunately, this requirement comes with a serious disadvantage, in that it
would force such studies to exclude patients with no remaining treatment
options. “Most clinicians and patient advocates will find this unacceptable,”
the authors write, “particularly for patients with very advanced disease who may
not survive long enough to see the new drug formally approved.” To circumvent
this, they say that active drugs—in the form of other experimental agents—“can
and should be provided through expanded access programs as these agents are
being developed.”
Rob Camp, a member of the Network Community Advisory Board of the AIDS Clinical
Trials Group (ACTG), appreciates the proposed study design. “Deep salvage is
where you can say that control data really isn’t the important thing,” he says.
“What we’re talking about is getting a positive result out of patients.”

Camp, however, isn’t so sure that single-arm studies should soon replace
randomized, controlled trials involving salvage patients. “I still think we need
some safety data,” he says, referring to toxicity and side effect comparisons
that may only be possible in randomized, controlled studies.

The U.S. Food and Drug Administration (FDA), with its authority to say what
studies must be conducted before a new drug qualifies for approval, echoes
Camp’s concern. “Our division hasn’t had a chance to sit down and talk about
what they’re proposing,” says Kimberly Struble, medical team leader with the
FDA. “But I’d say that large single-arm studies would not be sufficient enough
for approval.”

Before drugs hit pharmacy shelves, the FDA currently requires three phases of
control-arm studies to evaluate the safety and efficacy of an experimental ARV.
But this process takes years, and though there are several new drugs and new
drug classes coming to market in the next year, advocates and doctors worry that
growing numbers of people with drug resistance will run out of options before
those drugs become available. While promising drugs are often made available to
treatment-experienced patients through expanded-access programs after the drug
has reached phase III of development, the single-arm approach, implemented in
phase II, would provide access to potentially life-saving drugs much earlier in
the process.

Camp agrees with the effectiveness of control trials but thinks salvage patients
should be treated differently. “At the end of the day,” he says, “we have in the
U.S. 18,000 people dying of AIDS every year. It hasn’t gotten lower in the last
eight to 10 years. Why is that? Maybe people just don’t have access to drugs of
any sort. Another reason may be that people don’t have active regimens. Can we
lower that number? That would be terrific.”

Is there a need to increase access to treatments for salvage patients? Options to do this?  Plusses, minuses, perspectives. Salvage patients that have exhausted current options may need an adjustment in the status quo. Some of these salvage patients participated in trials years ago that we all are now benefiting from. I think we owe those pioneers. Hank


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