Proposal: Monitoring Program for Early Rapid Testing of New AIDS Treatments


The Problem

With the development of protease inhibitors and other new
approaches for treating HIV disease, there are more potential
treatments, and many more combinations, which are worth
trying. At the same time, the resources available for
research, both public and private, may be shrinking. Efforts
toward small, rapid trials must be encouraged; still, it has
always been difficult to get even small trials of leading-
edge ideas off the ground. Usually they do not happen at all,
or take place only after months or years of delay.

The main task is to address the apathy and lack of commitment
that makes it so difficult to get studies done -- not to
learn to live with the problem. But also, there is always a
place for learning how to accomplish the most with limited
resources.

We propose a program for careful, consistent monitoring of
experimental treatments which are already being used by
patients and physicians. The goal is to greatly reduce the
time and cost of getting the first widely credible
information about the effects of new treatments,
combinations, and treatment strategies in people.

Background

The new therapies of interest are already being tried by
individual patients and physicians. Reports of results often
circulate anecdotally. But for many reasons it is difficult
to rely on these reports. For example:

(1) Our interview with Dr. Feigal (AIDS TREATMENT NEWS #219,
March 24, 1995) noted that even in the most research-
intensive settings, sponsored by the largest pharmaceutical
companies, there is concern that results of individual cases
may be reported selectively.

(2) Most experiences with new treatments are in a clinical,
not research, setting. Often there is no advance planning to
assure that the data will be credible to third parties.

(3) There is little standardization among clinical physicians
regarding which tests and laboratories to use, exactly when
to give the tests, how to keep compatible records, etc.

(4) Even if the data is completely in order for research
purposes, there is still the credibility problem of
convincing others of this. It is much more difficult for each
physicians' practice to establish research credibility
independently, than for one research organization to build
its credibility over time.

New therapies of interest are also tried in pharmaceutical
company development programs. Here there are different
problems:

(1) Leading-edge approaches are seldom considered, since the
needs of corporate drug development are different from those
of patient care. Usually the best to hope for is monotherapy
with one experimental agent, combined with approved drugs;
for example, see the current ICC protocol [Inter-Company
Collaboration for AIDS Drug Development], which at most
combines one experimental drug with two approved ones.

(2) Even unimaginative trials take excruciatingly long to
actually begin; again consider the ICC trials, starting only
now despite the high-level attention and support long put
into them.

(3) Early trials of new agents or new approaches often do not
measure viral load or any other indication of activity; or
they start by testing doses known to be ineffective. These
trials, by design, can only be pieces in a long, expensive
development process; no possible outcome could establish a
rationale for human use of any treatment.

When considering options in trial design, we should be aware
that certain limitations of randomized clinical trials have
long been known and analyzed in the medical literature, but
ignored in AIDS research.

Arvin R. Feinstein, from the Yale University School of
Medicine, examined these limitations in a paper published in
1983 ("An Additional Basic Science for Clinical Medicine: II.
The Limitations of Randomized Trials," ANNALS OF INTERNAL
MEDICINE, volume 99, pages 544-550); Robert J. Levine, in
ETHICS AND REGULATION OF CLINICAL RESEARCH, Yale University
Press, 1986, recommends that this article "should be
required reading for all persons who conduct or review plans
to conduct randomized clinical trials."

Feinstein noted that randomized trials have been successful
when studying treatments to remedy an existing condition, but
have "sometimes created rather than clarified controversy"
when used in studies of either primary or secondary
prevention of conditions which the patients do not have yet.
And there has long been a seemingly irreconcilable conflict
between "pragmatic" investigators (usually clinicians), who
want the trial to provide useful clinical information, and
"fastidious" investigators, usually biostatisticians, who
want a clean study.

Feinstein also considered many ethical and logistical
limitations of randomized trials. He concluded, "The
scientific resolution of most future problems in clinical
management will have to come from analyses of events and
observations that occur in non-experimental circumstances,
during the interaction of nature, people, technologic
artifacts, and clinical practitioners. By recognizing the
informal "experiments" that are done whenever a clinician
treats a patient, and by developing better observational
methods for acquiring and analyzing the data, clinical
investigators can be liberated from their previous
intellectual restrictions and can take the fundamental steps
needed to develop an additional basic science for clinical
practice."

Proposal: Monitoring Project

A research organization could implement a monitoring program
for systematic data collection, analysis, and reporting about
treatments of interest which are already being tried.

One way to both greatly decrease the cost of research, and
simultaneously increase its relevance, is to study the
treatments which physicians and patients have decided to use
anyway. Since the actual treatment is already planned or
underway, aside from the research project, the costs and
obstacles involved in making a human trial happen are not a
problem. Financially, the costs will be largely for lab work
and administration. But the real costs of any clinical
research includes not only the money, but also human costs
(including increased risk and lost-opportunity cost) of
asking patients and physicians do to something different from
what they would have chosen to do otherwise. By studying
treatments which would have been used in any case, this
larger cost is also greatly reduced or eliminated.

A protocol for this project would not specify the treatment
to be used, as the physicians and patients would choose that
in each case. The protocol might include formal selection
criteria for the treatments and the patients to be
considered. But since different patients' results will not
usually be averaged together, inclusion/exclusion criteria
need not be severe; the real question is whether there is a
clinically interesting question that might be addressed, and
this decision can best be made case by case by a medical
review board.

For example, such a project might study patients who are
trying to lower their viral load (plasma HIV RNA) by using an
experimental treatment or combination. Those entered into the
study would be given specified baseline and after-treatment
viral load tests -- as well as a physical exam, medical
history interview, and immunological and other tests widely
used in HIV trials. These results could be reported quickly;
but there might also be scheduled followup which continues
much longer (for example, through interviews at six months
and then annually, continuing indefinitely whether or not the
treatment is continued).

To avoid any question of selective reporting, everyone
accepted for study by the review board would immediately be
given a sequence number and be accounted for in the published
reports -- even if they never received the tests, or never
used the intended treatment. This is only a matter of
thoroughness of reporting; it does not affect statistical
results, since the different patients are usually not
averaged together.

Protocol Outline

The particular tests, schedules, and other details will
ultimately be chosen by the researchers. This outline is
intended as a basis for discussion.

Inclusion/Exclusion: Volunteers who are using antiretroviral
therapy must not change that therapy for at least a month
before beginning the treatment to be monitored by this
program. And they must be starting a treatment which might
affect the overall course of HIV disease; it could be an
antiviral, or work by some other mechanism, or have an
unknown mechanism. But treatments for opportunistic
conditions will not be studied in this protocol.

Tests: The primary test to be monitored will be plasma HIV
RNA, by the Hoffmann-La Roche quantitative PCR. Other
standard panels -- immunological, hematological, blood
chemistry -- will also be specified. A physical exam and
medical history will be given when the volunteer enters the
program, and a physical exam and exit interview (including
questions on compliance) at the end of the primary monitoring
period.

Visits: Ideally three baseline viral load tests will be
given; on the day treatment begins, half a week (3 or 4 days)
before, and one week before. Other baseline blood tests will
be included as necessary.

Length of Study: The primary monitoring period will be eight
weeks. After treatment begins, blood draws will be at half a
week, one week, two weeks, four weeks, and eight weeks. Test
results will not be batched or blinded, so that the volunteer
can use them in making treatment decisions, including whether
or not to stay in the monitoring program. Volunteers can
change their antiviral regimen and still remain in the
program.

Ideally the entire panel of tests would be given at each
blood draw; however, the protocol may specify reduced
testing, for economic or practical reasons.

Followup: After the primary monitoring period, the treatment
being studied may or may not be continued. In either case,
follow-ups will be scheduled at six months after treatment
began, one year after, and annually after that. Ideally each
followup would include the blood tests; but at a minimum,
followup could be by phone interview.

At the end of the primary monitoring period, results would be
published, or otherwise made available to other investigators
and physicians.

An Ethical Concern

When an individual case is reported, the person is easier to
identify than if they are one of many who are summarized
statistically. This problem may be reduced, if the only test
results reported are those done specifically for this
research; the numbers would not be identical with those in
the person's medical record. And some results might be
reported in summary form -- for example, percentage changes
might be given instead of absolute values in some cases. But
ultimately the volunteers will need to understand that this
research does not offer the anonymity of a large trial, and
accept or reject participation with that in mind.

Specific Questions

We believe that patients and physicians will find more
interesting treatments to test than we could list by
ourselves. But there is no harm in discussing some questions
that might be addressed by this kind of screening study.

AIDS TREATMENT NEWS occasionally publishes a list of about 30
treatments which have a valid rationale for testing in HIV
disease, are not in a major development project currently,
and are already widely used in people for other purposes
(making research much easier than with a new chemical); this
list last appeared in issue #218, March 3, 1995. In many
cases, the possible mechanism of action is not known, and
therefore it is not known how relevant a viral load test
would be for measuring drug effects. But it may still make
sense to include such treatments in an exploratory study
based on viral load; there is little cost of doing so, and
the results might give some insight into a mechanism of
action.

(1) For example, it would be interesting to see if viral load
can fall after a patient starts acyclovir (due to an indirect
effect of the drug, which is not believed to have anti-HIV
activity). Apparently no one has tried this yet. Any effect
on viral load might be seen in only some patients -- those
who have another virus which may act as a cofactor for HIV
and which is susceptible to acyclovir. Therefore, a single
negative result obviously does not mean that this line of
research should be abandoned; instead, a number of patients
will need to be tested.

(2) Another area where we do not know the mechanism concerns
micronutrients. Consumption of certain micronutrients (either
in food or in supplements) during asymptomatic disease has
been found to be associated with substantial delay in disease
progression, and increased survival; for other
micronutrients, no such effect was found (see "Some Vitamins
Associated with Decreased Risk of AIDS and Death." AIDS
TREATMENT NEWS # 214, January 6, 1995.) Could a well-designed
supplementation regimen (perhaps given by injection to avoid
absorption problems) have an effect which could be seen in
viral load reduction?

(3) Some physicians have suggested doxycycline as possibly
beneficial in AIDS treatment, for unknown reasons. Possible
mechanisms include controlling possible mycoplasma
infections, or treating other infections which may not be
diagnosed. These rationales are probably too weak to get this
drug into a formal trial, even a small one; but still it
would be interesting to see if there are any consistent
changes in viral load or other tests when patients start the
drug. We should remember that some of the most important
leads in the history of medicine have been completely
unexpected in advance. The proposed monitoring project brings
down the cost of research to the point where such a study
could happen.

(4) Hydroxyurea has had a strong rationale as an antiviral at
least since the Berlin conference over a year and a half ago,
but it has been notoriously difficult to get a formal trial
going, in part because no one has exclusive rights to the
drug. And the drug is dangerous enough that physicians who
are not experienced with it are reluctant to use it without a
good reason. Only recently have a number of patients started
to try it. With the proposed monitoring study in place, drugs
like this could be tested in a research setting as soon as
someone wanted to try them; if strong antiviral activity is
found, it would bring more attention to a potential
treatment. This is a drug that physicians can learn to use
safely, if they first have a reason for doing so.

(5) Ribavirin, a broad-spectrum antiviral, was rejected
prematurely as an AIDS treatment years ago, after an intense
conflict between the Commissioner of the FDA at that time,
and the president of ICN, the company developing the drug.
Ribavirin might have a role for some patients, especially in
combination with ddI or certain other drugs; and today, its
antiviral activity could be followed with viral load tests.
Despite continuing popular interest, ribavirin has not been
revived as a potential treatment because of the lack of
commercial motivation for organizing new formal trials. The
proposed monitoring project -- based on viral load testing,
which was not available when ribavirin was studied previously
-- could greatly reduce the cost of getting new credible data
about this drug.

(6) The monitoring project could also be used for early
information to guide clinical trials of combinations of
protease inhibitors or other drugs in mainstream development
-- combinations that would not otherwise be tested. One
important question here is the effect of these drugs and
combinations in people who already had much experience with
antiretrovirals, and were unable to lower their viral load
further with conventional treatments. The mainstream trials
are now focusing on antiviral-naive subjects; but the main
use of the new drugs, at least initially, will be for people
who have already failed other available treatments. We need
to know what combinations are likely to work in these
difficult cases, and we may not get that knowledge from the
trials currently planned.

The Next Step

This monitoring project should probably begin at one site
(AIDS Research Alliance [formerly SEARCH Alliance, in Los
Angeles] would be ideal); the tests and treatments could be
administered either there, or in the offices of physicians
associated with the organization. Later, other research
institutions or clinical practices might also use the same
protocol.

The first critical step is to refine this proposal and
develop a detailed protocol, incorporating the views of
medical and research experts.

A working monitoring project will mean that as soon as the
first patient is ready to try a treatment, that treatment can
be tested, with results becoming available almost
immediately. While the results from the first few patients
will clearly be limited, they will be completely consistent,
without selection bias, and collected exactly as specified.
If early results are favorable, more people will try the
treatment, strengthening the confidence in the results of the
monitoring, and also generating early interest in other
studies, including larger, controlled trials.