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AIDS Treatment News Issue #228, August 4, 1995
   phone 800/TREAT-1-2, or 415/255-0588

CONTENTS:

New Antiretroviral Strategies: Interview with Marcus Conant, 
M.D.

3TC: Now Available Again Up To CD4 of 300

California: Medi-Cal Can Pay for Human Growth Hormone for 
Some Patients

Boston: Important Trial of Treatment Vaccine, CD4 Over 500

FDA Workshop on Clinical Trial Design, Sept. 6-7 -- 
Registration by Aug. 18

AIDS "Confirmatory" Trials: What's Wrong, and How to Move 
Forward Today (see the "Comment: Workable Clinical Trials," 
in "FDA Workshop...," above)

FDA Reform: Activists' Proposals


***** New Antiretroviral Strategies: Interview with Marcus 
Conant, M.D.

by John S. James

Marcus Conant, M.D., heads the Conant Medical Group, one of 
the largest HIV practices in San Francisco. 

AIDS Treatment News: How has your approach to treating HIV 
infection changed since a year or two ago?

Dr. Conant: Today when we find that someone is HIV positive, 
we are using three indicators, instead of one or two, to try 
to measure where they are in the course of the disease.

Historically, the first measurement we had of disease 
progression was symptoms. It was obvious that people who had 
fever, fatigue, weight loss, night sweats, who started 
developing skin conditions or other diseases, were further 
along in the course of the disease, and therapy might be 
instituted then. If someone was doing very well and suddenly 
developed a yeast infection, even if they didn't have any 
symptoms, even if the CD4 (T-helper) count had not dropped 
greatly, that would tell us that their immune system was not 
working as well as it had before, because they could not 
suppress the yeast any more. 

Then it became clear that the CD4 count -- or better, the CD4 
percentage -- was an important indicator. So we measured CD4 
about every four months. The most sophisticated patients knew 
that it wasn't a drop in the number that was important, it 
was a drop in the percentage.

The classical indicators that had been used in medicine, the 
history, the physical findings, and the laboratory studies 
(particularly the CD4 count or percentage, in the case of HIV 
infection) were what we used until last year to decide who 
should go on therapy. So if a patient had a CD4 count of 800 
and was totally asymptomatic, we did not initiate therapy. If 
someone had a CD4 count of 550, but had a lot of fatigue, and 
had had zoster a year ago, and then had developed hairy 
leukoplakia, many of us would have gone ahead and put that 
patient on combination therapy -- saying that the CD4 counts 
looked good, but because of the increase in symptoms and 
signs, we had clinical evidence of HIV disease progression, 
and we now needed to be more aggressive.

Viral Load Testing

In the last year we have added viral load to the formula. So 
now we are looking at symptoms, measuring the CD4 count, and 
also looking at viral load. While the information has become 
more complex, it has actually become easier to use, because 
the viral load can give us more information than all of the 
others put together.

If we saw a patient who was totally asymptomatic, had no 
physical finding, no cutaneous or other infections suggesting 
disease progression, and had a very high CD4 count, say 800, 
and had a viral load measured by branched DNA (bDNA) or 
quantitative PCR at less than 10,000 copies, we would not 
treat that patient, but would repeat the branched DNA test 
every four to six months. If at any point one of the markers 
started telling us this patient was progressing -- if the 
branched DNA, for instance, suddenly went up to 40,000, or 
the CD4 count dropped precipitously, or the patient started 
getting lots of symptoms -- then we would likely decide to 
start therapy.

[Note: The branched DNA test -- abbreviated bDNA -- is one 
technology for measuring the viral load, the number of copies 
of HIV RNA per milliliter of blood plasma. Other technologies 
for measuring the viral load are quantitative PCR, and NASBA. 
Incidentally, each HIV virus particle has two copies of its 
RNA, so the actual number of copies of the virus is half the 
number of copies of HIV RNA.]

ATN: If the viral load suddenly goes up, would you repeat the 
branched DNA or other viral load test?

Dr. Conant: In my experience, the bDNA test is very 
reproducible, far more reliable than the CD4. So if I get a 
bDNA that is elevated, I usually do not repeat it a month or 
two later to see if it is accurate; instead, I respond to it. 
But if the patient was totally asymptomatic and had a stable 
CD4 percent, and the bDNA count went sky high, say from 
10,000 to over 100,000, then I would retest to make sure a 
mistake had not been made.

Initial Antiviral Treatment

ATN: What antiviral therapies are you using first?

Dr. Conant: If there is evidence of disease progression, we 
are first treating many patients with very high dose d4T. The 
dose I usually start with is 20 mg. twice a day; then I have 
the patient increase it by 20 mg. each week, until they get 
neuropathy, or until we get to 80 mg. twice a day. That is 
twice the FDA-recommended dose.

Why are we going that high? The answer is that the 
recommended dose of 40 mg twice a day was picked because that 
was the dose at which 50 percent of the patients in the early 
trials developed neuropathy. But the studies also showed that 
you got a four-fold increase in antiviral effect, every time 
you doubled the dose; from 40 to 80 total daily dose, you get 
a four-fold increase in suppression. So if patients can 
tolerate the dose, I go all the way up to 80 mg per day. And 
in people with high CD4 counts, we can get to 80 in almost 
all the patients. We are not seeing much neuropathy, if the 
patient is asymptomatic with a high CD4 count when you start 
aggressive treatment with d4T.

Once I get to the maximum dose of d4T, then about a month 
later I repeat the bDNA test. With CD4 counts, we used to 
wait four months or so before repeating it. But with viral 
load, there is clear evidence that you can see measurable 
decreases within two weeks of initiating effective 
antiretroviral therapy. By a month you ought to be able to 
get a good measure.

Say we had a patient whose viral load had gone from less than 
10,000 to 40,000 copies, and we put him on 80 mg of d4T, and 
a month later we measured it, and it is less than 10,000 
again. We would continue that patient on the therapy, seeing 
him or her at least once every four months, reassessing where 
we are with their antiviral measurement -- and reassessing 
their history and physical signs, and CD4 count.

If we see viral escape -- if the viral load starts going up 
again -- I would add ddI to the d4t, and I would continue 
that, monitoring every four months.

AZT and 3TC

If the patient's CD4 count still drops -- and if it drops low 
enough so that they could qualify for the 3TC expanded-access 
program -- we often put those patients on AZT plus 3TC. But 
we wait to start AZT until we could start 3TC simultaneously. 
Because it did not seem to make sense to put them on AZT 
alone for a year or two, let the virus get resistant to that 
drug, and then add the drug that helps to prevent the 
emergence of resistance.

If the patient could not qualify for the 3TC access program, 
I would probably wait, and continue to play with d4T and ddI 
-- and maybe even add saquinavir -- and hold the AZT until I 
could combine it with 3TC.

ATN: How is this different from your approach a year or two 
ago?

Dr. Conant: The change in view you are hearing from me is 
that we have traditionally used AZT as the first drug of 
choice. That was the first drug we had, and we continued to 
use it first. And yet, nothing says that we cannot first use 
drugs that may not be as effective as AZT, and use up their 
efficacy, and then go to stronger drugs later on.

If tomorrow the FDA approved 3TC, then I would probably begin 
with a combination of AZT plus 3TC plus ddC, much earlier in 
the course of the disease.

But in San Francisco you have an aging epidemic; most 
patients have experienced these drugs in some dose, for some 
period of time, over the last five years. So my 
recommendation is that the patient and physician sit down, 
find the drugs that were tolerated the best, and try to 
combine two or perhaps three of those. For example, if the 
patient could take AZT and had no problem with ddC, combine 
the two drugs, and see what happens to the viral load. If the 
viral load goes down, monitor them every four months; and if 
the viral load starts going up again, shift to ddI and AZT. 
Play with the drugs to get the viral load down as low as 
possible.

With saquinavir now available on expanded access, if I were 
the patient, even though that drug in the dose being used is 
not as effective as the new protease inhibitors coming along, 
I would add that to my cocktail, using the bDNA about a month 
after I changed to see how effective the treatment was. If 
the viral load goes down, great; then I would wait another 
four months and check it again.

ATN: The Consensus Symposium on Combined Antiviral Therapy is 
being held in Lisbon July 25-27. My concern is that there is 
not much consensus, and we might end up with a lowest common 
denominator kind of recommendation.

Dr. Conant: More and more my colleagues are using similar 
strategies. They are starting with combinations earlier, and 
they are using bDNA to tailor what the combination is.

ATN: I have heard of a few people who had very low CD4 counts 
who were treated with AZT plus 3TC, and in a few cases their 
total lymphocyte count went way down, but the CD4 and CD8 
counts stayed about the same or decreased only a little. Have 
you noticed any problem like that, perhaps where the 
hematological toxicity of AZT was getting amplified?

Dr. Conant: We have not seen that. In our experience, 3TC has 
been the best tolerated of the antiretrovirals. Many patients 
feel better after they start taking it. There can be problems 
with peripheral neuropathy -- especially in patients who have 
had peripheral neuropathy in the past. And there are 
occasional reports of minor dizziness, hair loss, or joint 
pains.

CD4 Percent Vs. CD4 Count

ATN: You mentioned that the CD4 percent is actually a better 
measurement that CD4 count, even though the latter is the one 
generally used. With CD4 percent, what danger points do you 
watch for? And could you explain why the percent is the 
better measure?

Dr. Conant: When the CD4 percent goes below 20 I start 
getting concerned.

We need to keep stressing to patients that if your CD4 count 
drops a little -- from 300, for example, down to 230 -- then 
look at changes in your CD4 percent. If the percentage was 21 
percent, and the count dropped to 230 but you still have 21 
percent, there really has not been a drop. 

This is because of the way the CD4 count is calculated. You 
start with the white blood count and see what percent of 
those cells are lymphocytes. Then you see what percent of 
those are CD4 cells. For example, if your white count is 4000 
per milliliter, and your percentage of lymphocytes is 50 
percent, then that means that 2000 of the cells are 
lymphocytes. And if the percent of lymphocytes that are CD4 
cells is 25 percent, that means that 500 of them were CD4 
cells, so your CD4 count would be 500.

Why is the CD4 percent more important than the CD4 count? 
Because your white blood count can vary from hour to hour, 
just because of time of day, or exercise, or a small 
infection. If the white blood count changes for these minor 
reasons, it may look like the CD4 count has gone down or up. 

It is well known that the percentage is most important; and 
yet patients, unfortunately, are still stuck on the number. 
We doctors did that; we continued to talk in terms of numbers 
instead of percentages, although as early as 1988, at the 
International Conference on AIDS in Stockholm, it was clear 
that percentage was really the most important figure.

Future Directions

ATN: Where do you see AIDS treatment heading in the near 
future?

Dr. Conant: We are very excited about both the Abbott and the 
Agouron protease inhibitors. We are seeing drops in viral 
load of two to three logs (100 to 1000 fold), and preliminary 
data suggests that those reductions are sustained for 
extended periods of time, without the emergence of 
resistance. I would predict, based on the data we are seeing 
today, that we may well see protease inhibitors, instead of 
nucleoside analogs, as the first line of therapy.


***** 3TC: Now Available Again Up To CD4 of 300

In April, Glaxo (now Glaxo Wellcome) restricted its expanded-
access program for 3TC, due to unexpected demand and a 
resulting shortage of the drug. The most important 
restriction instituted at that time is that patients had to 
have a CD4 (T-helper count) under 100, instead of under 300, 
to qualify. But now there is more drug, and starting in late 
August, persons with a CD4 up to 300 can qualify again -- but 
those with counts under 100 will still be given priority.

A total of 650 new participants per week will be allowed in 
the program, instead of only 350, as has been the case from 
April until late August. Physicians will still need to submit 
lab slips to verify CD4 count, as they have had to do since 
April.

Note: The decision to give priority to persons under 100 
reflects sentiment at two community meetings of persons with 
HIV and their advocates, which Glaxo called to discuss how 
best to handle the unexpected drug shortage. It was not an a 
priori decision of the company.

A Glaxo spokesperson told us that since the beginning of the 
open-label program, over 24,000 people have been enrolled. A 
large but unspecified number of them are also taking AZT. The 
spokesperson acknowledged that many participants are also 
combining 3TC with ddI, ddC, or d4T, or with various non-FDA 
approved treatments, such as NAC or hydroxyurea. She said 
that Glaxo cannot endorse or encourage these other 
combinations.

Meanwhile, enough data has been collected from controlled 
trials of 3TC that a New Drug Application (NDA) was filed 
with the FDA on June 30. Glaxo Wellcome, the newly merged 
company, is requesting that 3TC, combined with AZT, be 
approved for treating individuals with CD4 counts below 500.

To register as a clinical investigator in the 3TC Open Label 
Program, physicians should call 800/248-9757. Registering new 
patients can be done by fax, and the drug is shipped within a 
few weeks. The blood draws required by the protocol are 
largely routine, and the paperwork required to monitor 
participants is not unreasonable.


***** California: Medi-Cal Can Pay for Human Growth Hormone 
for Some Patients

by John S. James

As this issue goes to press, AIDS Treatment News has heard 
that Medi-Cal will pay for human growth hormone through the 
Serono treatment IND, for some patients, starting August 1. 
Serono will start processing Medi-Cal applications on that 
date. Physicians and patients will still apply for the 
program in the same way, by calling the Serono phone number 
below, as Serono handles the reimbursement paperwork.

To qualify for the Serono program (regardless of whether or 
not one is applying for Medi-Cal reimbursement), a physician 
must determine that a patient has AIDS-related wasting, with 
loss of at least 10% of body weight. The patient must be on 
antiretroviral treatment, and must be 18 or older. Until 
recently, the program also required the patient to fail both 
Megace and Marinol, which are FDA-approved for wasting; but 
due to a recent protocol amendment, patients now must only 
fail one of those drugs, and that requirement can be waived 
if the physician determines that both of them are medically 
contraindicated.

In order to enroll patients, a physician must first qualify 
as a site with Serono. Later, less paperwork is required to 
add each individual patient. Physicians should begin the 
process by calling the Serostim Information Line, 800/714-
AIDS (800/714-2437).

Patients also can call this number for information.

Comment

As is often the case in AIDS care and activism, a number of 
people behind the scenes deserve particular credit for making 
this potentially life-saving treatment more available.


***** Boston: Important Trial of Treatment Vaccine, CD4 > 500

A trial at Beth Israel Hospital in Boston is seeking 18 
volunteers for a trial of a new kind of treatment vaccine. 
Volunteers must have a CD4 (T-helper) count over 500, no 
antiretroviral use for six months prior to entering the 
study, no use of immunosuppressive agents, and must be 
asymptomatic and generally in good health, and not become 
pregnant during the trial.

The vaccine is a peptide (small part of a protein) found in 
HIV, attached to a lipid (fat) "tail"; it is made entirely by 
chemistry, not from live HIV. This vaccine has been tested in 
a few HIV-negative volunteers; it appeared to be safe, and it 
caused the body to produce HIV-specific CD8 CTLs (cytotoxic T 
lymphocytes) -- cells which may specifically kill some HIV-
infected cells. It is hoped that this vaccine may delay 
progression of HIV disease -- but this is a theoretical 
possibility which has not yet been proven.

There are two parts of this study. In part I, six volunteers 
will receive one injection of either low dose vaccine, high 
dose vaccine, or placebo, and the study will last 32 weeks. 
In part II, other volunteers will receive up to three 
injections, and the study will last 36 weeks. In both parts, 
there is at least a two-thirds chance of getting vaccine 
instead of placebo. Everyone will have physical exams, 
various lab tests, and HLA typing (the tissue typing used for 
organ transplants); those in part II will also have viral 
load tests and measurements of CTL responses. For part II, 
some but not all of the volunteers will need to have certain 
specific HLA types to qualify.

The vaccine is being developed by United Biomedicals, Inc., 
of New York. The principal investigator of the study is 
Norman L. Letvin, M.D. The official title of the study is 
"HIV Lipopeptide Immunotherapeutic in HIV-1 Seropositive 
Human Subjects." Participants will receive a small payment, 
$20 per visit plus $5 for parking.

For more information, contact Joan Callery, R.N., at 617/667-
3351.


***** FDA Workshop on Clinical Trial Design, September 6-7 -- 
Registration by Aug. 18

by John S. James

The FDA will hold a public workshop on the design of HIV 
clinical trials, September 6-7, 8:30 a.m. to 5:00 p.m., in 
Bethesda, Maryland. Following the workshop there will be a 
joint meeting of subcommittees of the Antiviral Drugs 
Advisory Committee and the National Task Force on AIDS Drug 
Development, on September 8. Both meetings will be held in 
the William H. Natcher Conference Center, at the National 
Institutes of Health, in Bethesda, Maryland.

Purpose -- and Background

This workshop and the associated meetings will focus on 
dealing with the difficulties of designing "confirmatory" 
trials to use after accelerated approval of a drug. Under the 
accelerated approval system -- which was developed and 
implemented by FDA commissioner David Kessler -- new drugs 
can be approved based on "surrogate marker" indications of 
efficacy -- usually blood tests such as viral load or CD4 (T-
helper) count. These treatments are then fully approved and 
can be marketed like any approved drug, and are reimbursed by 
insurance; the only difference is that, in return for 
approval based on blood tests, the accelerated approval 
regulations require that the company agree to perform 
confirmatory studies, after approval, to prove that the drug 
has real clinical benefit to patients. In practice, this has 
been taken to mean proving efficacy by "clinical endpoints" 
-- deaths or AIDS-defining opportunistic infections.

For various reasons, these confirmatory trials are turning 
out to be unusually difficult to do. For example, how do you 
get people to volunteer for a body-count study, to prove -- 
through their deaths or serious illnesses -- a drug which has 
already been generally accepted in the practice of HIV 
medicine? The goal of this workshop, according to its 
official announcement, "is to discuss the critical issues in 
the design and conduct of clinical confirmatory trials in HIV 
and to propose strategies to overcome identified obstacles so 
that new drugs can be made available more quickly and that 
information on how to best use them also be obtained without 
unnecessary delay."

Deadlines

Registration for the workshop is required by August 18, by 
fax to 301/443-9216 (with your name, organization if any, 
address, and phone number) or by Internet. Persons wishing to 
speak at the Advisory Committee meeting should telephone by 
August 25. After the meetings, persons may submit comments on 
the workshop until October 31, by mail or Internet. Because 
of the messiness of the additional details, we decided not to 
publish them here, but to refer interested persons to Heidi 
Marchand or Kimberly Miles, Office of AIDS and Special Health 
Issues, 301/443-0104.


***** Comment: Workable Clinical Trials [or, AIDS 
"Confirmatory" Trials: What's Wrong, and How to Move Forward 
Today]

It appears that this workshop (see FDA Workshop on Clinical 
Trial Design, September 6-7 -- Registration by Aug. 18) has 
been requested to address profoundly wrong issues. It is 
being asked to design trials to meet the requirements of the 
accelerated approval regulations. Worse, the official 
announcement of the workshop includes the statement, "In HIV, 
the clinical endpoints that have been considered meaningful 
are survival and disease progression as manifested by the 
development of AIDS-defining opportunistic infections." As we 
will show below, this statement reflects the fundamental 
error which has made AIDS clinical trials unproductive. If it 
becomes the focus or agenda of the workshop, then nothing 
valuable will emerge.

We believe that the real reason confirmatory trials are 
proving so difficult is that the kind of confirmatory trials 
which are now being designed and run should not be done at 
all. The accelerated approval regulations, when Kessler 
introduced them several years ago, were a tremendous advance 
over what existed before. We and many others have strongly 
supported them. But now it is time to move on. We may not 
even need to change the accelerated approval regulations -- 
let alone abandon them. But we do need to interpret them in a 
way which is productive for today. We need confirmatory trial 
designs which are rational and cost-effective in the light of 
current knowledge.

Today -- even though it has not yet been officially "proven" 
in a formal, academic sense -- there is in fact an ever-
growing, unmistakable if not overwhelming practical sense 
that modern surrogate markers do mean something. In case 
after case, when viral load goes down, good things happen 
clinically -- for example, symptoms of many different kinds 
go away, and HIV infected mothers with low viral load do not 
transmit the virus to their babies. Long-term survivors are 
usually people who have low viral load naturally. Researchers 
may not have prospectively "proven" that patients who 
maintain a viral load under 10,000 copies due to drug 
treatment live longer than if they let their viral load stay 
at 500,000 or a million, but the reason for the lack of such 
proof is that no one has done the study. Who would volunteer 
to be left with the high viral load until something happened 
to them? And even if volunteers could be found, it would take 
some time to complete such a trial, because it would take 
time for enough people to develop AIDS-defining infections or 
die. We do not have that time. But quite a number of bright 
people are now designing just this kind of study -- the 
stylish "strategy" trial -- with the expectation of finishing 
it before "confirmatory" trials, as currently understood, are 
allowed to go away.

What needs to be done now is to break the irrational mind-
set, which started early in the AIDS epidemic and has 
continued as if on autopilot ever since, that clinical proof 
of a drug (that is, proving that the drug really helps 
patients, not just improves blood tests) requires clinical 
endpoints (understood as death or AIDS-defining opportunistic 
infections). In other words, instead of starting with mostly 
healthy people and waiting until they get AIDS-defining 
illnesses or die, start with people who are clinically ill, 
and whose symptoms are easily measurable and not intolerable, 
and see if the antiviral treatment in question can get them 
better -- can make their symptoms go away. This is clinical 
proof of drug efficacy -- proof that the drug does help real 
patients, not just blood-test numbers. And at the same time, 
this kind of trial uses the easily measured symptoms as a 
"marker" for more profound activity of the drug.

Admittedly this kind of trial would not prove survival 
benefit. We can afford to do without this proof because, as 
time moves on: (1) we are becoming more confident that the 
survival benefit is in fact there, even though it would be 
very difficult and ethically questionable to prove it for 
sure; (2) the cost of trying to prove survival is continually 
increasing, and the feasibility of doing so is becoming less, 
as patients have more treatment options open to them; (3) if 
we are wrong about survival benefit -- if a particular 
treatment lowers viral load, and raises CD4 count, and also 
makes clinical symptoms go away, and yet does not affect 
survival -- doctors would soon recognize this incongruity, 
and such a very surprising finding would provide invaluable 
leads in pathogenesis research; and (4) the drugs could be 
justified even in the unlikely case that they did not prolong 
survival, as they would have been formally proven to improve 
quality of life.

The one truly bad consequence of the unlikely possibility of 
being wrong about survival benefit (when viral load, CD4, and 
disappearance of clinical symptoms all do show treatment 
benefit) is that thousands of patients may choose a treatment 
which turns out not to keep them alive longer, when otherwise 
they might have chosen one which did help keep them alive. 
But this worst possible scenario is no worse, and may be less 
bad, in the system we are proposing than in what exists now. 
For in the current system, where confirmatory trials have to 
prove survival (or AIDS progression) benefit, the drug is 
already approved; thousands of people are using it before its 
failure to improve lifespan is known. In our proposed system, 
the long, slow survival-type confirmatory trial is replaced 
by a rapid, symptom-reduction confirmatory trial. Since this 
trial takes weeks instead of years, doctors get the symptom-
reduction information almost immediately. If a treatment 
makes people healthier in every measurable way, including 
clinical symptom reduction, but still they die as fast with 
the drug as without, then physicians will probably realize 
that something is wrong, due to the unexpected deaths, and 
shift to other treatments, even before any survival trial 
results could be ready.

The kind of confirmatory trial we propose -- seeing if an 
antiviral treatment relieves existing AIDS-related symptoms, 
instead of seeing if it delays progression to AIDS or death 
-- not only can be done in weeks instead of years, but also 
needs a few dozen or fewer volunteers, not hundreds. And this 
kind of trial can ethically use a placebo control -- 
scientifically the best control -- provided that the symptoms 
are tolerable, and that the volunteers freely choose to risk 
enduring them for a few additional weeks, in order to 
contribute to science. No one we have talked to, including 
some hard-line skeptics, has been able to find any 
fundamental problem with this approach to confirmatory 
trials. But still the trials do not happen, the idea does not 
translate into reality, into a far better system for doing 
confirmatory studies, because inertia is strong and no 
institutional machinery exists to oppose it.

If it really is so easy, why wasn't this done years ago? We 
do not know. Perhaps the wrong ways of doing things were 
enshrined by necessity early in the epidemic, and then became 
a religion for many.

This writer will probably attend the September 6-8 meetings. 
We are reluctant, fearing yet another waste of time, because 
for years we have addressed meeting after meeting with little 
result -- little or no input into the ongoing national 
conversation about clinical trial design, about AIDS 
research, about why AIDS research has been unproductive, 
about how it could be made to work better. People are set in 
their ways. Ongoing political battles, often addressing 
obsolete issues, have a long history, and the combatants are 
now dug in.

If you might also attend the meetings, or send a statement, 
and will help me to get the above message heard, let me hear 
from you.


***** FDA Reform: Activists' Proposals

by John S. James

A number of proposals for changing the FDA -- mostly to get 
treatments to patients faster -- or to avoid changing the FDA 
in ways people do not want, are now circulating in Washington 
and across the country. This article looks at reform efforts 
by AIDS activists. Also, a number of FDA reforms have already 
been introduced in Congress; and industry, government, and 
other organizations and individuals have also proposed 
reforms.

It is important for the AIDS community to know what ideas are 
on the table, so that our interests can be represented in 
this discussion.

AIDS Community Proposals

We know of three major proposals on FDA reform initiated by 
AIDS activist organizations. Unfortunately, despite some 
overlap in people and recommendations, the three groups have 
seldom talked to each other. This disunity reflects long-term 
divisions over AIDS treatment policy.

We will describe these three FDA proposals in more or less 
chronological order:

The "Principles of FDA Reform"

A consensus letter on FDA reform is now being circulated for 
sign-on by AIDS and other organizations. This letter lists 11 
(originally 12) principles proposed as the basis for any FDA 
reform.

The 11 principles:

* "The FDA's mission should remain protection and advancement 
of public health.

* "Federal regulation of the safety and efficacy of drugs, 
diagnostics, medical devices, and biotechnology products is 
essential.

* "FDA must allow pre-approval access to experimental drugs 
that show promise for serious and life-threatening diseases.

* "FDA must regulate drugs for serious and life-threatening 
diseases differently than drugs for routine and treatable 
diseases.

* "Post-marketing research is a critical component of drug 
development and regulation.

* "FDA approval provides a foundation of knowledge, upon 
which present and future doctors and patients decide how, 
when and in whom to use the drug.

* "FDA must retain regulatory flexibility.

* "FDA must ensure data are gathered on all populations 
likely to use a new drug.

* "While retaining its independence, FDA must be held 
accountable.

* "FDA must have sufficient resources to perform its duties.

* "FDA and industry must collaborate and communicate 
effectively in all phases of drug development."

The consensus letter with these 11 principles, including 
short explanations of each, has been signed by ten major AIDS 
organizations, mostly located in or with a presence in 
Washington.

While these principles themselves are designed to be 
inoffensive and hard for anyone to disagree with, this effort 
to focus the AIDS community's involvement in FDA reform has 
not been free of controversy. A number of people -- including 
some who signed on, despite personal doubts, after 
negotiating some changes in the wording -- are concerned that 
this list fails to ask for what we as a community want. They 
signed this letter to show unity, but with the expectation 
that specific, positive reforms would also be put on the 
table for national discussion, in a separate document (see 
"FDA Reform Consensus Statement," below).

While a number of people from the ten signing organizations, 
and some others, developed the eleven principles, the 
Treatment Action Group (TAG) is generally regarded as the 
main organizer of this effort. Derek Link, in a Dear 
Colleagues letter from Gay Men's Health Crisis, explained:

"... The philosophical underpinning of these principles is 
that legislative changes to FDA's statutory authority are not 
needed for effective and responsible FDA reform. We need 
further FDA reform, but the Republican Congress is not the 
place for us to achieve this. The message is that we still 
need to push for FDA reform, but that we can do it directly 
with the FDA not with Mr. Gingrich. It is important for 
everyone to remember that the FDA regulates 25% of everything 
we buy -- that is, the core things in life (drugs, food and 
beauty products!). FDA regulates some very large and powerful 
interests. FDA reform in the Congress is not about people 
with serious diseases, it's about making life easier for the 
drug industry, agribusiness, and Revlon. The Republican 
Congress does not have our interests at the top of its list 
of priorities. Once FDA's legal authority is opened up by the 
Congress, it will be quite dangerous. Well-funded lobbyists 
for all sorts of corporations will attempt to manipulate the 
process in ways that may be in opposition to our needs."

For a full copy of the Principles of FDA Reform, to sign on, 
or for additional information, contact Derek Link, 212/337-
3502.

FDA Reform Consensus Statement Draft

This very different document is a draft of a consensus 
statement being prepared by five AIDS activists, mostly on 
the West Coast. It focuses on what many people in the AIDS 
community want most -- avoiding unnecessary delays and 
streamlining the process of getting new treatments to people 
faster. "The thinking behind it," according to Martin Delaney 
of Project Inform, one of the authors, "is to find places to 
squeeze chunks of time out of the drug development and 
approval cycle." He described it as focusing on specific 
areas where we can make practical progress today, without 
dismantling the overall system.

The current draft addresses five different areas: Improving 
compassionate access; Accelerated approval refinements; 
Institutional review board approval of phase I academic 
research; Creation of an appeals process; and Information 
distribution about off-label drug use. Because this proposal 
is too long to reproduce in full in AIDS Treatment News, we 
quote the entire introduction and then summarize the five 
areas.

The introduction:

"There is a public groundswell for FDA reform and a multitude 
of approaches are currently being proposed. For individuals 
facing life-threatening illnesses, broader and earlier access 
to promising therapies is a critically important outcome of 
any FDA reform effort. While we recognize the need for the 
FDA to regulate the safety and efficacy of new drugs, we also 
believe that the agency's overall regulatory mission must 
appropriately address the differing needs and values of 
people with life-threatening illnesses, carefully balancing 
risk versus benefit. We believe that the needs of life-
threatened patients, for example people with AIDS or cancer, 
warrant greater risk-taking in the drug development process. 
For these individuals, we advocate the fastest cycle of drug 
development possible without needlessly endangering their 
safety. We strongly believe that people whose lives are 
immediately threatened by disease or illness should have the 
fundamental right to access the most promising therapies in 
development when they have failed or have become intolerant 
to all standard therapies.

"As people with AIDS and their advocates, we respectfully 
submit the following proposal and urge its adoption for all 
life-threatening illnesses, without prejudice for or against 
any other proposals currently under consideration before 
Congress or the Administration."

* On compassionate access, the FDA should "routinely 
encourage" not only parallel track programs after phase I 
(dosage and toxicity testing) has been completed and the 
first "surrogate marker" efficacy indications are available, 
but also emergency access for individuals even before the 
completion of phase I.

* The FDA's current program of "accelerated approval," while 
it has been successful, can be improved by resolving several 
bottlenecks identified by experience. To avoid months of 
delays, the FDA should not use advisory committees for all 
accelerated-approval decisions, but only when "unusual safety 
risks" or "truly new scientific issues or processes" are 
involved. FDA should encourage companies to apply for 
accelerated approval (for treatments for serious or life-
threatening conditions) based on data from a single well-
controlled study, and should "routinely grant preliminary 
marketing approval based on summary data within 30 days of 
submission of an NDA (New Drug Application) for drugs 
designed for life-threatening illnesses."

* University-based institutional review boards should be 
allowed to approve academic (non-commercial) trials, freeing 
FDA staff to approve other trials more quickly. "In the past, 
most purely academic clinical research not associated with 
commercial product development has been initiated upon the 
authority of local Institutional Review and did not require 
IND (investigational new drug) applications and approval from 
the FDA. In recent years, there has been a growing tendency 
to shift responsibility for approving such research back upon 
the FDA. One consequence of this is that the queue awaiting 
approvals for commercially sponsored research is longer than 
ever..."

* Drug developers should be able to appeal FDA decisions. 
"Decisions made by the FDA presently are final and without 
opportunity for appeal, a process unlike almost any other 
aspect of the American legal or regulatory systems." Sponsors 
who challenge a scientific decision of FDA staff should be 
able to call for a hearing, or call for the appointment of a 
panel of independent experts. The FDA would have to accept 
the decision of the appeals board. Sponsors would pay the 
costs of the process if their appeal was rejected.

* Companies should be allowed to inform doctors about "off 
label" uses of approved drugs, when supported by peer-
reviewed, published research. "It is well established that as 
much as 40% of all drug use occurs off-label and that some of 
the most important uses of drugs are not defined by their 
label indications. Current agency practice forbids sponsors 
from providing any information to physicians about such use 
of drugs..."

For a copy of the current draft of the FDA Reform Consensus 
Statement, or to make suggestions for this effort as it 
evolves, send a fax to the Linda Grinberg Foundation, 
310/471-4565.

Republican AIDS Activists Proposals

San Francisco AIDS activist Jim Driscoll, who is the leading 
AIDS expert for the Log Cabin Republicans (a gay Republican 
organization in Washington, D.C.), and also for the Progress 
and Freedom Foundation (a think tank associated with 
Representative Gingrich), has for several months discussed 
FDA reform with Congressional offices preparing bills on the 
subject.

Driscoll told us that he is most interested in four specific 
reforms:

* The mission of the FDA should be amended, so that the 
agency makes it its business not only to protect the public 
against unsafe or ineffective drugs, but also to encourage 
the rapid development of medical science and technology.

* University-based institutional review boards should be 
allowed to approve early clinical trials, in most cases, 
without FDA approval also being required.

* Drug companies should be allowed to educate doctors about 
well-accepted off-label uses of their products.

* Congressional intent on the efficacy standard should be 
made explicit, to insure accelerated approval of drugs for 
AIDS, cancer, and other life-threatening conditions.

"FDA Reform will speed AIDS drug development by reducing 
bureaucratic hitches in phase I clinical testing, and by 
streamlining FDA review," Driscoll told AIDS Treatment News. 
"Reform can also reduce the cost of drug development, which 
means that the same amount of research funding can test more 
drugs and combinations. Research avenues now neglected as too 
costly will be explored. Those who raise the red flag of 
safety concerns need to remember that, due to scientific 
advances, including drugs which are better targeted, drug 
testing is far safer today than it was 20 or 30 years ago.

"But FDA is more interested in protecting itself and 
expanding its bureaucracy than in saving the lives of 
patients with AIDS and cancer. It is time for Congress to put 
patients above bureaucrats and hold FDA strictly accountable 
for the human as well as financial costs of bureaucratic 
delays. Legislative reform of the FDA is the surest way to 
speed a cure for AIDS."

For more information on Log Cabin Republican regulatory 
reform efforts, call Jim Driscoll, 415/552-0269.


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