kdavis@apple.com (Ken Davis) (07/05/89)
AIDS TREATMENT NEWS Issue # 81, June 29, 1989
CONTENTS
News Flash 6/28: Unofficial "Compound Q" Study
Montreal Conference: Overview and Comment
Roxithromycin Fails in Advanced Toxoplasmosis
San Francisco: DDC Trial Seeks Volunteers
Long Island: July 9 Fundraiser for Community Groups
Please Return Hypericin Surveys: Deadline Extended to July 15
In Memoriam: Barry Gingell
Why No Antivirals: A Case History of Failed Trial Design
NEWS FLASH 6/28: UNOFFICIAL "COMPOUND Q" STUDY
A so-called "secret study" of trichosanthin, the experimen-
tal AIDS treatment also called Compound Q, became a focus of
national controversy after one of the patients died. All indica-
tions so far are that the drug did not contribute to the cause of
death. But the controversy has furthered a much- needed national
discussion over the design and implementation of clinical trials
during a public-health emergency.
The project, a treatment program organized by Project Inform
of San Francisco, included very thorough monitoring of laboratory
test results and the clinical condition of over 30 patients in
four U.S. cities, treated by their physicians with trichosanthin.
The drug was obtained from China, where it has been widely used
for almost two decades. All patients received the lowest dose
used for any purpose in China; this dose was repeated three times
at weekly intervals. The patients selected were very ill and had
failed all other treatments. No one was charged anything to par-
ticipate; all labor and expenses were donated by the physicians,
or by Project Inform or others.
While early indications are promising, Project Inform
emphasizes that it is too early to tell if trichosanthin will be
useful as an AIDS treatment; the organization hopes to make a
full report available in one to two months. Also, the drug is
similar to chemotherapy and can cause severe side effects in some
patients; it must not be used without proper medical supervision.
A major reason for organizing this monitoring project was that
people were already using the drug as an AIDS treatment, with
unknown and potentially serious risks.
We will cover the trichosanthin monitoring study (and the
debate around it) in depth in future issues. Meanwhile, readers
can learn the basic facts from newspapers such as the San Fran-
cisco Chronicle, San Francisco Examiner, The New York Times, and
the Los Angeles Times.
Comment
This monitoring study is as thorough, professional, and
careful as any trial we have seen, and it promises to be a turn-
ing point in efforts to control the AIDS epidemic. It shows that
clinical trials can develop useful information very quickly when
they are organized to do so, and when patients are well informed
of the unavoidable risks and willing to accept them.
If trichosanthin turns out to be valuable as an AIDS treat-
ment, then this project could save thousands of lives. Everyone
involved deserves our gratitude and support.
MONTREAL CONFERENCE: OVERVIEW AND COMMENT
by John S. James
The "V International Conference on AIDS", June 4-9 in Mont-
real, was the major AIDS conference of 1989. We have found it
difficult to cover this meeting.
Why the difficulty? With over 5,000 papers on AIDS
presented, we could easily have filled several issues with
interesting facts and stories, each one safely documented. But
these would have been isolated stories with no particular use or
relevance. We want to present this information within a meaning-
ful framework.
The widespread myth of objectivity, a myth cultivated to
support the status quo, has obscured the fact that viewpoints,
interpretations, or relationships can be an essential tools for
effective communication, not just extraneous opinion. The lack
of coherent, well-formed viewpoints explains the seeming paradox
of having simultaneously too little AIDS information, and too
much. Persons seeking information are flooded with unconnected
facts but unable to find what they need.
It is hard to cover the Montreal conference because
viewpoints must be constructed for this purpose. No single theme
emerged.
As many as fifteen official meetings ran simultaneously,
together with hundreds of poster presentations, as well as press
conferences and private or miscellaneous meetings. We had to
choose certain areas, and leave important subjects to others. We
did not focus on AZT, for example, because we knew that many phy-
sicians would be paying close attention to this treatment, and
therefore important developments would probably not be lost.
Instead, we sought information which could be overlooked by the
mainstream, but which the AIDS community might use to save lives.
Several different themes emerged as most important:
(1) Lack of progress on getting new drugs ready to use;
(2) Promising drugs in the research/approval pipeline;
(3) More information (mostly negative) on certain "alternative"
treatments;
(4) New treatment ideas; and
(5) Access issues, including early treatment and developing coun-
tries.
Lack of Progress
The central impression from the conference is disappointment
at the lack of productivity of the clinical-trial system during
the last several years. Dozens of promising drugs are in the
research/regulatory pipeline; the problem is getting them out of
the pipeline.
Two years ago, when the same conference was held in Washing-
ton, D.C., some of the AIDS physicians said, "Next year, in
Stockholm." A year ago, after the Stockholm conference, it was,
"Maybe next year, in Montreal." This time we did not hear the
same expectations for the 1990 conference in San Francisco. The
experimental drugs are more promising than ever. But people are
learning that the research designs now in use could not possibly
release important antivirals for years even when we already have
every reason to believe that the drugs are safe and probably will
make an important contribution to therapy.
The world according to press releases designed by public-
relations professionals is a world where everybody involved
shares a sense of urgency, and is proceeding as fast as good sci-
ence will allow, but no faster. In this world, new treatments
could appear almost any time, as if by magic. But a look behind
the press releases at the actual design and operation of clinical
trials shows clearly that there will be no decisive advances in
AIDS treatments by the 1990 San Francisco conference, or the 1991
Florence conference either, if the design and management of tri-
als continues as it is going today.
Fortunately, the impediments to productivity are becoming
more clear. Our article below ("Why No Antivirals: A Case His-
tory of Failed Trial Design") analyzes as a case history an
upcoming trial of the major antiviral which is furthest ahead in
the clinical-trials pipeline. We show why it would be almost
impossible for this drug (or any other major antiviral) to be
ready within two years, even though there are dozens of candidate
drugs which appear promising in laboratory, animal, and even
human studies unless a widespread professional consensus about
how to design trials of AIDS drugs can be changed. We show why
the trial was designed the way it was (making rapid results
impossible), what assumptions motivated this design, where those
assumptions are wrong, and what can be done instead (or in addi-
tion).
The central problem is not with any one agency, company, or
other institution, but with a professional consensus which
crosses organizational boundaries and if not changed, will stop
any decisive treatment advance from being available for years.
Instead of waiting until the 1991 Florence conference, for exam-
ple, to ask once again why there are no new antivirals to replace
or supplement AZT, we can raise the issue now. Some of the
failures of upcoming trials are so predictable that we can
analyze them before the trials even begin when some of the prob-
lems might be bypassed or avoided instead of waiting years to
only recount the same failures after they have happened.
The professional consensus which guarantees lack of results
has been allowed to persist because of national and international
lack of leadership on treatment development, lack of commitment
to saving lives. In the United States, for example, 97 percent
of the 5,100 largest foundations have not given one penny to AIDS
(December 1988 report of the Foundation Center, cited in May 17
talk by Dr. Timothy Wolfred, outgoing executive director of the
San Francisco AIDS Foundation); of the three percent which have
contributed at all, it is well known that most will not touch
research or research advocacy. This lack of commitment, so
clearly seen in the above tabulation, operates less openly behind
the technical complexities of human trials, the legitimate need
for caution and control in human research, the cleverly concocted
press releases, and the widespread lazy assumption that the
experts know best and therefore no further thinking or action by
anyone else is necessary.
It is understandable that people and institutions are reluc-
tant to look closely at clinical trials, a complex, technical
area where human life is at stake. But in the resulting vacuum,
the failure of national leadership and commitment has combined
with pre- existing problems in the medical and research systems
to lead to a "conventional wisdom" which includes assumptions
which guarantee that the clinical-research system will fail to
respond to the AIDS public-health emergency.
Something can be done. When the AIDS community is well
informed, it can bring key issues into the open and force them to
be addressed. Our "Why No Antivirals" article, below, shows the
precise errors and design flaws which guarantee that an upcoming
clinical trial will fail to meet the needs of the AIDS emergency,
no matter what happens in the trial. Since this study is one of
the better ones, and since the drug itself is ahead of all the
important antivirals in the regulatory pipeline, the flawed
assumptions and design illustrated in this trial almost guarantee
that no decisive advance in AIDS treatment will be available for
years even though the drugs which will be available then are in
many cases already well known today.
This issue has not been widely understood; until the Mont-
real conference, we ourselves did not see it clearly. By
detailed understanding and by persistence, the AIDS community can
force key weaknesses in trial design and administration to be
addressed, force the spokespersons for the conventional wisdom to
state the case for their positions before other medical and
research professionals. When their case is weak, the profes-
sional consensus which controls clinical research will shift, and
much faster shepherding of drugs through the research and regula-
tory system can quickly become possible.
Outline on Promising Treatments
Many attenders at the Montreal conference (including this
writer) agreed that DDI may be the most important single drug in
the AIDS research pipeline now. Most of the information
presented was not new, but confirmed previous informal accounts
(see "DDI Information Published", AIDS TREATMENT NEWS # 78, May
5, 1989). We are still analyzing the conference information, and
will follow DDI closely in the future.
Compound Q was not discussed at the conference, although one
abstract was published (abstract number C.596).
Soluble CD4 received much favorable attention in talks by
Robert Gallo, M.D., and other researchers. So far, however, the
efficacy results have been disappointing. While we are not list-
ing this treatment as one of the most promising, some of the
scientists who have worked with it remain enthusiastic about this
line of research, especially later generations of the drug.
Two posters were presented and three other abstracts were
published on hypericin, which continues to look good, although it
received little attention at the conference. No human results
were included, since no human research has yet been completed.
There were many posters on treatment of opportunistic infec-
tions. Except for pneumocystis prophylaxis, the most important
single drug was probably fluconazole, a broad- spectrum antifun-
gal used in Europe but still not marketed in the United States.
We will report further on promising treatments in future
issues.
New Information On Non-Approved Treatments
Treatment possibilities which look less attractive now than
they did before the Montreal conference include ribavirin,
isoprinosine, dextran sulfate, AL 721, and roxithromycin. Often
the new information is ambiguous, so we want to study it further
before writing a report. We cover roxithromycin, which failed in
treating advanced toxoplasmosis, below.
New Treatment Ideas
A number of new ideas were presented, especially in some of
the poster presentations.
For example, scientists at the University of Pittsburgh
tested an organic arsenic compound which had been used to treat
syphilis before penicillin was available (abstract number
M.C.P.133). The compound, oxophenarsine, was found to be
extremely effective against HIV in the test tube, in concentra-
tions as low as 0.035 micrograms/ml. According to one of the
presenters whom we met at the poster, it is the only drug known
to be able to block the virus in chronically-infected H9 cells.
In a similar test, AZT showed no antiviral effect.
We asked about toxicity, as some of the early syphilis
treatments were notorious. This one was apparently not as bad as
some of the others.
One advantage of this drug, which was once FDA approved, is
that much information about human use is already available, pub-
lished in old medical journals.
Unfortunately no pharmaceutical company anywhere still
manufactures this drug, which was used by injection. The Pitts-
burgh scientists are trying to get the original manufacturer to
produce enough for a test. Since the original patent rights have
long since expired, other companies could legally do so; the drug
is easy to make. (The University of Pittsburgh has applied for a
use patent for HIV treatment, in order to make the project
attractive to investors and obtain financial support.)
Oxophenarsine could be tested quickly and inexpensively to
see if it might be helpful as an AIDS antiviral. Unfortunately
it is more likely to be overlooked and ignored, regardless of
merit. Few people have both the capability and incentive to make
anything happen toward getting this potential treatment tested.
We hope that this article will bring the drug and the project for
its development to wider attention.
ROXITHROMYCIN FAILS IN ADVANCED TOXOPLASMOSIS
On March 10, AIDS TREATMENT NEWS reported that roxithromycin
had been found effective in treating toxoplasmosis in mice, and
had also been found to reach extremely high concentration in
brain tissue when the drug was given to humans scheduled to
undergo neurosurgery (so that the brain concentration could be
measured). This preliminary work suggested that roxithromycin
should be tried as a treatment for toxoplasmosis. We could only
find one human case where the treatment had been tried, however,
and the result was inconclusive. No trials were planned in the
United States, where 20,000 to 40,000 cases of toxoplasmosis have
been predicted by 1991 (Luft and Remington, "Toxoplasmic
Encephalitis", The Journal of Infectious Diseases, January 1988).
We mentioned that we had heard a report that a small trial would
soon begin in France.
At the Montreal conference, physicians from a hospital in
Paris reported that they gave three times the usual dose of rox-
ithromycin to eight patients who could no longer tolerate
pyrimethamine/sulfadiazine (P/S), the conventional treatment for
toxoplasmosis (poster # W.B.P.29 in the conference abstracts).
However, symptoms of toxoplasmosis reappeared after 28 to 45 days
of treatment. In four of these eight patients, P/S treatment
could be started again, and it was successful. The conclusion
was that the roxithromycin was not effective.
In addition, on June 6 a French physician wrote to us that
roxithromycin had been found ineffective, at least when used
after cerebral abscesses had already formed, although he noted
that it might prove useful earlier.
SAN FRANCISCO: DDC TRIAL SEEKS VOLUNTEERS
A major national study comparing DDC (dideoxycytidine) with
AZT for treatment of persons with AIDS or severe ARC is now
recruiting patients at Davies Medical Center in San Francisco.
This trial will also take place in other cities, but we have been
unable to obtain a list by press time.
DDC (not to be confused with DDI) is an antiviral like AZT,
but it works in much smaller doses. Early trials used doses
which turned out to be too large, causing peripheral neuropathy
in some patients. In the new trial with reduced doses, the side
effects are expected to be small and manageable.
To be accepted for the study, volunteers must have fewer
than 200 T-helper cells, have no KS, and either had pneumocystis
within four months before starting the trial, or have certain
other AIDS-related symptoms. They must not have used AZT, and
not have used acyclovir for long periods.
Although participation is free, patients must be on monthly
aerosol pentamidine, which the study will not pay for.
This trial could begin in San Francisco as early as mid
July. For more information call Brian Christianson, 415/565-
6153.
LONG ISLAND: JULY 9 FUNDRAISER FOR COMMUNITY GROUPS
"Sunday by the Bay," a benefit for community-based research
and for AIDS service organizations, will take place July 9 in
Bellport, Long Island. This event, which will center around the
auction of items donated by well-known artists, is the third in a
series of successful fundraisers; last year's raised $170,000.
Beneficiaries this year again include the Community Research Ini-
tiative and the Long Island Association for AIDS Care, among oth-
ers.
Some of the money will also be used for small start-up
grants for AIDS organizations in locations where AIDS services
are hard to find.
For more information about the benefit, call 516/286-1020.
If you are interested in applying for a start-up grant, write to
Don Hall, People Taking Action Against AIDS (PTAAA), Box 378,
Bellport, NY 11713.
PLEASE RETURN HYPERICIN SURVEYS: DEADLINE EXTENDED TO JULY 15
We have extended the deadline for the hypericin survey (see
AIDS TREATMENT NEWS #80) to July 15. If you or a friend has any
experience with hypericin (usually available in St. John's wort
extracts), please return the survey or any other information to:
Survey, AIDS TREATMENT NEWS, P.O. Box 411256, San Francisco, CA
94141. We will publish the results in this newsletter. All
identifying information will be kept confidential, of course.
IN MEMORIAM: BARRY GINGELL
Dr. Barry Gingell, who died last month at age 34, was a New
York activist, physician and PWA who inaugurated the invaluable
publication Treatment Issues for the Gay Men's Health Crisis. He
embodied the idea of empowerment for people with HIV and AIDS,
working to make drugs like ribavirin and isoprinosine accessible
as early as 1985. His leadership in advocating aggressive and
intelligent treatment choices will be very much missed.
WHY NO ANTIVIRALS: A CASE HISTORY OF FAILED TRIAL DESIGN
by John S. James
AZT provides limited benefits to persons with AIDS or HIV,
and many people cannot use it at all. Many promising new
antivirals have long been in the research and regulatory pipe-
line: for example, DDI, AZDU (CS-87), D4T, DDC, hypericin, and
trichosanthin (compound Q). None has become available since AZT
was released almost three years ago. And at the Montreal AIDS
conference earlier this month, we learned why none will become
available for years unless certain current practices in the
design of clinical trials can be changed. This article will
illustrate some of the problems, and suggest solutions.
The basic problem lies not in any single agency, company, or
other institution, but instead in a conventional wisdom which
cuts across institutional boundaries. A professional consensus
guides the design and conduct of clinical trials, and the
shepherding of experimental drugs through the testing system.
This consensus today includes certain assumptions which make it
impossible for the existing system of clinical trials and drug
approval to respond successfully to AIDS as a public-health emer-
gency.
Note and disclaimer: Readers may notice that this issue of
AIDS TREATMENT NEWS has a call for volunteers (above) for the
same trial analyzed below as an illustration of a failure of the
clinical-trial system. This is not an oversight or contradic-
tion.
This trial is no worse than other AIDS studies. It seems to
be ethical in its treatment of volunteers. The problem is that
it will not produce results for years. But for now it is the
trial we have, so we must support it.
For the same reason, this article is not intended as a cri-
ticism of persons conducting this trial, nor of it's sponsor.
They have done well within the system of shared assumptions which
controls all mainstream AIDS research. It is this system which
needs reform.
A Case History: New DDC Trial
DDC (dideoxycytidine), an antiviral like AZT but with dif-
ferent toxicities, is not the most important new drug. But it is
farthest ahead in the drug-approval pipeline among major
antivirals. Because it is ahead of the others, and plans for a
major new study have been revealed, it provides an excellent case
study of the problems which will impede the approval of all
important new antivirals, not only DDC but also more interesting
drugs such as DDI.
DDC Background
DDC, like most of the new AIDS antivirals, was discovered to
have anti-HIV activity by U.S. Government scientists. The United
States then asserted exclusive worldwide rights, and assigned
these rights to a pharmaceutical company (in this case,
Hoffmann-La Roche, Inc. of Nutley, New Jersey).
Several trials have already been conducted. In early stu-
dies, some patients developed severe peripheral neuropathy, caus-
ing numbness or pain in the feet. Later human studies found that
lower doses could reduce P24 antigen levels, a sign of antiviral
activity, with manageable toxicity.
On June 5, 1989, Hoffmann-La Roche announced new trials,
designed in cooperation with the FDA (U.S. Food and Drug Adminis-
tration). A major phase II trial, which could lead to marketing
approval for the drug, will compare low-dose DDC head-to-head
with AZT "in persons with AIDS or advanced ARC."
The problem with this trial is that because of the design
chosen, it is unlikely to produce any conclusion for two and a
half years.
And since DDC is ahead of all other major antivirals in the
drug- approval pipeline, and the delays in this study design are
generic to AIDS antivirals and not specific to DDC, it is likely
that all major new AIDS drugs will face a similar delay. This
fact alone strongly suggests that no major new treatment for AIDS
will come out of the drug-approval pipeline for years, unless the
assumptions currently guiding clinical trials can be changed.
An analysis of the design of the new DDC/AZT comparison
trial, and the assumptions behind this design, will show exactly
how this intolerable situation came about, and how it can be
changed.
DDC Rumor: A Treatment IND?
Rumors have circulated that DDC may become more available
through a "treatment IND" before the end of 1989. We hope these
rumors are true.
But we are skeptical. The FDA has interpreted the treatment
IND very conservatively, using it only near the end of efficacy
trials, when the drug is almost sure to get full marketing appro-
val after the final paperwork is complete. If this procedure is
followed for DDC, a treatment IND will probably be more than two
years away, as we will show below.
The record is full of comforting but broken promises that
things have changed and therefore AIDS research will move faster
in the future. When the future arrives, the public has forgotten
the promises.
Why will the trial take so long?
This new phase II trial will compare DDC with AZT, using a
randomized, double-blind design. No placebo will be used; every
patient will get one of the drugs. The trial is scheduled to
last two years; recruiting the subjects is expected to take about
six months in addition.
In theory, the study could end earlier. A team of experts
will periodically monitor the results, secretly breaking the code
to see if there is statistical proof that patients getting DDC
are doing much better or much worse than those getting AZT. In
practice, however, for reasons explained below, it is almost
impossible that this study will end this way. The researchers
expect it to take the whole two years.
The reason that the study will take so long must be
explained in several steps:
(1) The FDA will not approve a drug based only on "surrogate
markers", meaning improvement in blood work such as reduction in
P24 antigen, or T-cell rises. The FDA also wants statistical
proof that the drug is helping people.
(2) After rejecting surrogate markers, the FDA has insisted
on the slowest measure of clinical improvement "clinical end-
points", meaning OIs (opportunistic infections) or deaths. This
means that the drug being tested is not measured by improvements
in the patients who receive it, but OIs or deaths in those who do
not.
The DDC trial will compare that drug with AZT. Since AZT
works fairly well for the first year, the number of deaths and
OIs in the control (AZT) group will be low. Therefore, even if
the drug being tested were perfect and everybody taking it were
cured instantly, the clinical trial design would not recognize
that fact until enough deaths and OIs had accumulated in the con-
trol group to provide statistical proof that DDC was no worse
than AZT.
(3) This study, like some others, will use a team of experts
(sometimes called a "data safety monitoring board") to meet
periodically and secretly break the code and examine the results
so far, to see if the study should be ended early. The public is
told that such reviews can end studies as soon as statistical
proof of effectiveness is obtained.
But in practice it is unlikely that this or any similar
study will be ended early. The reason why not involves an eso-
teric problem in statistical interpretation. If researchers take
an early look at their data to decide whether to stop the study
early and call the drug a success, but then decide that the data
does not justify stopping, meaning that the study will run to its
normal conclusion, then the very fact that they looked early
means that they must tighten their interpretation of the final
results. A drug which otherwise could have been considered a
success might now need to be counted a failure just because the
researchers looked at the data and might have acted on that
information even though in fact they did nothing different as a
result of the look.
This seemingly preposterous conclusion is hard to explain
even to scientists, let alone to readers with no statistical
background. We will try to do so; those who are not interested in
the details can skip the next four paragraphs.
[When researchers claim statistical proof that their drug
works, they are usually claiming that the drug passed a test
which only a small percentage of worthless drugs could have
passed by chance; the smaller the percentage, the better. For
example, if a journal article claims that a result is "statisti-
cally significant at the p<0.01 level," this means that the pro-
bability (p) that a worthless drug could have done as well or
better by chance alone is less than one percent (0.01).
What happens, then, if you look at the data early? Suppose
that the researchers did not know about the problem that we are
describing here, and they decided to take an early look at their
data, and end the trial immediately if the drug was good enough
to have reached the p<0.01 level already. If not, they would
continue the study and see if they achieved that level later.
Clearly then the chance of accepting a worthless drug at
some time in their trial would now be greater than one percent.
This is because there is a full one percent chance to accept such
a drug at the early look and if the worthless drug did not pass
the test at that time, there is some additional chance that it
could pass later. Since the overall probability of accepting a
worthless drug is now greater than one percent, the researchers
cannot correctly claim that their trial showed efficacy at the
p<0.01 level. To honestly make that claim, the researcher must
use a higher standard both for the early look, and also at the
normal end of the study (if the early look did not result in the
trial's termination).
This means that if researchers take an early look at their
data but decide not to end the study as a result, they then must
tighten their standard for judging a drug successful later.
Drugs which would otherwise have been judged effective will
therefore now be rejected. Clinical trial design can minimize
this problem by making the early look be as conservative as pos-
sible.]
The practical effect of this statistical oddity is that
researchers have a strong incentive to use an extremely conserva-
tive criterion for ending a study early. As a result, a "data
safety monitoring board" provides less protection to the
volunteers in a study than they may be led to believe. And the
assurance to the public that experts are monitoring the trial and
will end it as soon as the data justifies, thereby speeding final
approval of the drug, is largely empty.
(Note: The AZT trial was stopped early in September, 1986,
when there were 16 deaths in the placebo group, vs. only one
death in the AZT group. No one knows why this extreme difference
occurred, as later experience does not support a 16 to one
difference in death rate with AZT. And despite this great
difference in deaths, the decision to stop the study then has
been controversial.)
During the Montreal conference, Hoffmann-La Roche conducted
a press conference on DDC. The speakers were Thomas Merigan,
M.D., principal investigator at the AIDS Clinical Trial Group at
Stanford University, and Whaijen Soo, M.D., Ph.D., director of
clinical virology at Roche. Few reporters came to this meeting,
which was a mile away from the main conference. Our impression
from the discussions at that press conference is that nobody
expected the study to end before two years.
The important question is not whether to end studies early.
It is whether the best way to prove a drug is to wait for deaths
and OIs in those who do not receive it. This trial design makes
studies inherently slow, whether they are ended early or not.
No one at the press conference raised the issue of whether a
study design which will take more than two years to get results
is an acceptable public health response to the epidemic. We are
concerned that all the important AIDS antivirals are behind DDC
in the pipeline. If they suffer the same delay as DDC, then we
can almost guarantee that no major new AIDS antiviral will be
generally available for at least two years.
Recruiting Problems Likely?
One of the problems with many AIDS clinical trials is that
entry criteria are designed purely for scientific reasons,
without thought as to whether there will be patients available to
fit them. As a result, many studies take much longer than
intended, or even fail altogether, because of recruiting diffi-
culties.
The DDC study may have this problem. Volunteers must have
less than 200 T-helper cells, and also have had pneumocystis in
the last four months or have certain ARC symptoms. And yet they
must have never taken AZT. Most people will have already tried
AZT before they have severe symptoms and under 200 T- helper
cells.
Some may have never taken AZT because they chose not to.
But they would be unlikely to volunteer for this study because 50
percent of the people enrolled, chosen at random, will go into a
control group and receive AZT instead of DDC.
It seems that the only volunteers left would be those who
never took AZT because they could not afford it; in the study,
the drug is free. But these people face another problem. The
study also requires use of aerosol pentamidine, but will not pay
for it. If persons could not obtain AZT in the past, how will
they obtain aerosol pentamidine for the next two years into the
future?
It would seem that these conditions, taken together, sys-
tematically exclude almost everybody from the trial. A few might
get through, such as those whose first contact with the medical
system is pneumocystis.
Notice how much of the problem with this study, including
recruitment, stems from the decision to prove DDC by counting
"clinical events" (deaths and OIs) in the control group. To get
clinical events, the patients must be seriously ill although
never treated with AZT. But once on the study, for ethical rea-
sons they must receive an antiviral and pneumocystis prophylaxis,
reducing the clinical events and therefore requiring more
volunteers (therefore a multicenter trial) and a two-year dura-
tion. All this to get enough deaths and OIs to allow the drugs
to be compared.
An alternative would be randomized, double-blind trials
designed to use patients' overall clinical condition as the out-
come measure, not deaths and OIs. The problem seems to be that
academic researchers do not trust physicians' evaluations in out-
come measures in their experiments even within a double-blind
trial because such evaluations involve some subjective element.
A body-count outcome sounds more scientific.
THE IDEOLOGY AND PUBLIC RELATIONS OF CLINICAL TRIALS
Having looked at the reality of the modern phase II clinical
trial for AIDS antivirals, we will now look at the image. The
image is important, because it is used to calm the public, jus-
tify the existing system, and impede calls for reform.
The DDC press packet from Hoffmann-La Roche provides a con-
venient look at this image. Any other public relations from a
mainstream clinical trial would be similar, however, as govern-
ment and other controls have imposed a research monoculture.
Even the public front is uniform.
From a June 5 press release we learn that "Everyone colla-
borating on this project at Roche, the FDA and the National
Institutes of Health is intensely aware of the urgency for
developing safe and effective treatments for AIDS. Awareness of
that urgency constantly compels us to work together as expedi-
tiously as possible toward definitive results." We also learn
that "Initial studies suggest that DDC may have an antiviral
effect at the low doses that result in manageable toxicity. The
studies now being planned are essential if we are to turn sugges-
tions into medically useful conclusions."
An undated Dideoxycytidine (DDC) Fact Sheet includes a ques-
tion and answer section on the availability of DDC. We quote it
at length because it illustrates several aspects of the currently
prevailing ideology of clinical trials.
"Q: When will DDC be available?
"A: That depends largely on the results of the new trials. When
dealing with human life, the adverse effects profile and optimum
dosage of a drug must be carefully studied no matter how urgent
the need. As soon as the clinical data warrant, Roche will file
a New Drug Application (NDA).
"Meanwhile, each of the new trials has entry criteria specific to
its design, and some of the studies already have their full com-
plement of volunteer patients. People who would like to partici-
pate in, or simply learn more about, the trials should call FDA
(sic) at 800/874-2572 (800/TRIALS-A) or Roche (collect) at
201/235-2355.
"Q: Will Roche provide DDC on a compassionate plea basis?
"A: The urgent need for more effective weapons against HIV weighs
heavily on everyone associated with this project at Roche, the
FDA, and the NIH. However, at present, we are agreed that the
clinical data now available are insufficient to justify distribu-
tion or use of DDC against AIDS outside of carefully controlled
clinical trials. Only new data can change this situation. Con-
sequently, we are working closely together to expedite the next
round of therapeutic trials, from which the medically necessary
data will flow.
"Q: When will Roche submit an NDA for DDC?
"A: Roche will submit an NDA as soon as the data from the pivotal
studies allow. A special review board will continually evaluate
data from all of the trials and make appropriate recommendations
to FDA."
Some points to note about the world of AIDS treatment
research according to press releases:
(1) Everyone involved feels urgency, and is working well
with everyone else. (During the press conference, however, this
reporter could find no shred of evidence of urgency.)
(2) More studies are, of course, essential. (300 people
have already been given DDC in clinical trials,.)
(3) The phrase "no matter how urgent the need", in the con-
text of justifying withholding a drug until more studies collect
still more information about "the adverse effects profile and
optimum dosage", clearly illustrates the fact that no weighing of
costs and benefits (of the extra studies and their associated
delays) will be considered. Instead, persons with AIDS can sim-
ply get lost until the researchers are finished. In theory they
might join the study, but in practice less than one percent of
persons with AIDS or related conditions will be able to do so.
Incidentally, the dose has already been determined well
enough to bet this entire phase II study on it, as only one dose
will be used in this study.
(4) Unless they qualify for a trial, patients and their phy-
sicians have no role in the decision of whether or not to use a
drug, until someone is ready to sell it to them. This decision
is made for them, by agreement between government officials and
potential vendors. For AIDS, the answer is almost always no.
Other diseases have been treated more liberally.
(5) The public is not told that the reason the trial will
take so long is that deaths and OIs must be accumulated.
Instead, the public is told that the trial might not take two
years but could end any time, because experts will watch over it
and pull the plug as soon as medically possible, moving the drug
to the next step in the approval pipeline. As we have seen, this
study will almost certainly take more than two years.
(6) The Dideoxycytidine (DDC )Fact Sheet also said that the
first comparison trial was expected to "begin" in July and last
up to two years, "depending on results". Readers might assume
that the maximum delay for this trial is therefore two years and
one month. This assumption would be wrong.
The six months for recruiting subjects was an informal esti-
mate mentioned by one of the researchers at the press conference.
Past experience suggests that it is probably optimistic.
Note that a trial which "begins" in one month and lasts "up
to" two years may take far longer than 25 months to be finished.
This is because the trial "begins" with the recruitment of the
first subject, but the two-year clock starts only with the
recruitment of the last. In addition, multicenter trials often
have recruitment quotas for different centers, meaning that the
clock starts only when the slowest center is ready.
The difference recruitment can make is illustrated by a
study of Imuthiol (DTC). Over two years ago, on April 10, 1987,
AIDS TREATMENT NEWS reported that this six-month study was under-
way. Most centers recruited patients promptly and completed
their phase of the study. But because of stragglers, this six-
month study was still running two years later, and the data from
those subjects who completed the trial long ago has not been
released.
The point is that press releases about clinical trials are
designed to provide a comforting picture of reality. Since clin-
ical research is a forbidding area complex, esoteric, and involv-
ing risk to human life few in the media or elsewhere have looked
behind the image. It is much easier to trust the experts.
Because of lack of understanding of what is really going on,
people are repeatedly surprised at the lack of new drugs for
AIDS. Those who do look will realize that the current system of
clinical trials could not possibly meet the needs of the AIDS
emergency, and is very unlikely to release even a single impor-
tant new AIDS drug for years even though the drugs are there.
The drugs which will provide the important treatment advances of
1992 and 1993 are already available and quite well known we named
some of them above. But DDC will take over two years for the
upcoming trial alone, and all the other important antivirals are
behind it in the pipeline, so they will take longer still.
THE CENTRAL ISSUE
The key reason no new antivirals are available is that clin-
ical trials have waited for deaths and OIs, instead of looking
directly at clinical benefit, which with some drugs is dramatic.
Conservative trial designers have used deaths and OIs because the
numbers seem more "scientific" than clinical ratings, which
depend in part on judgments of physicians, and may not be identi-
cal from one researcher to the next; by contrast, everyone can
agree precisely on the number of deaths in the treatment and con-
trol groups. However, "softer" kinds of data such as average
ratings by panels of experts have been handled successfully in
many fields of science. When we are looking for dramatic
effects, as with DDI or Compound Q, these methods have more than
enough precision to do the job.
The AIDS community must continue to raise the issue of
whether counting deaths and OIs is truly the only legitimate way
to tell whether an AIDS antiviral is working. Using "surrogate
markers", such as T-helper cell count or P24 antigen level, is
one approach to faster study design.
But we fear that surrogate markers alone are not enough that
to try to use blood work as the sole basis for approving new
drugs would lead to a long and unproductive argument. A middle
ground, which we believe will be most productive, is to use sur-
rogate markers and also direct measurements of clinical benefit
in persons taking the drug, such as numerical ratings based on
examinations by physicians. The variability in the course of the
disease, sometimes cited in arguing against this approach, can be
controlled for by double-blind designs, and by well-known sta-
tistical methods. The purpose here is to find the dramatically
effective drugs, the home runs, and to test them quickly; slower
study designs are acceptable when researchers are looking for
minor or marginal differences.
The issue of surrogate markers is already receiving serious
professional attention. But the related issue of the reluctance
of trial designers to use direct measures of clinical benefit as
proof of efficacy of AIDS antivirals, instead of insisting on
deaths and OIs in the control group as the only important meas-
ure, has been largely overlooked. The AIDS community must insist
that this issue be considered on it merits, as this key reform
will allow the most important new AIDS antivirals to be tested
many times faster than by the methods now in use.
STATEMENT OF PURPOSE
AIDS Treatment News reports on experimental and complemen-
tary treatments, especially those available now. It collects
information from medical journals, and from interviews with
scientists physicians, and other health practitioners, and per-
sons with AIDS or ARC.
Long-term survivors have usually tried many different treat-
ments, and found combinations which work for them. AIDS Treat-
ment News does not recommend particular therapies, but seeks to
increase the options available. We also examine the ethical and
public-policy issues around AIDS treatment research.
HOW TO SUBSCRIBE TO AIDS TREATMENT NEWS
Send $100.00 per year for 26 issues ($150.00 for businesses and
organizations), or $30.00 reduced rate for persons with AIDS or
ARC who cannot afford the regular rate, to: ATN Publications,
P.O. Box 411256, San Francisco, CA 94141. A six-month subscrip-
tion (13 issues) is $55.00 ($80.00 for businesses or organiza-
tions), or $16.00 reduced rate. For subscription information and
a sample issue, call (415) 255-0588. For the complete set of
over 70 back issues, send $75.00 ($18.00 for persons with AIDS or
ARC) to the above address. The back issues include information
on hypericin, dextran sulfate, foscarnet, passive immunotherapy,
DTC (Imuthiol), naltrexone, DHEA, lentinan, propolis, coenzyme Q,
monolaurin, egg lecithin lipids, fu zheng herbal therapy, DNCB,
aerosol pentamidine, fluconazole, ganciclovir (DHPG) and other
experimental or complementary treatments.
To protect your privacy, we mail first class without mentioning
AIDS on the envelope, and we keep our subscriber list confiden-
tial.
Outside North America, add $20.00 per year for airmail postage,
and $18.00 airmail for back issues. Outside U.S.A., send U.S.
funds by International Postal Money Order, or by travelers
checks, or by drafts or checks on U.S. banks.
Copyright 1989 by John S. James. Permission granted for non-
commercial reproduction.
--
Ken Davis - W6RFN San Francisco, California
UUCP: (apple, pyramid, netsys, pacbell, hoptoad}!lamc!kdavis
DIALCOM: 164:MDU0116 Internet: lamc!kdavis%apple.com