
AIDS TREATMENT NEWS #243, March 15, 1996
   phone 800/TREAT-1-2, or 415/255-0588

CONTENTS:

Indinavir (Crixivan(R)), Merck Protease Inhibitor, Approved

Ritonavir (NORVIR(TM)), Abbott Protease Inhibitor, Approved

Protease Inhibitors at FDA Advisory Hearings

FDA Antiviral Hearings: Community Perspectives

FDA Hearings: For More Information

Human Growth Hormone Not Recommended for Approval on Narrow 
Advisory Panel Vote

Consensus Statement on the Further Development of Protease 
Inhibitors And Human Growth Hormone

AIDS and Alternative Medicine, Seattle, April 28


***** Indinavir (Crixivan(R)), Merck Protease Inhibitor, 
Approved

by John S. James

FDA approval of indinavir, Merck's protease inhibitor, was 
announced on March 14; the drug is expected to be available 
by March 25. For several months, indinavir will be made 
available under a temporary special distribution system, 
primarily through Stadtlanders Pharmacy. Merck's price to 
wholesalers will be $12 a day, or $4380 per year (retail 
prices are not known as this issue of AIDS TREATMENT NEWS 
goes to press). This price is significantly less than the 
prices of the other two protease inhibitors now approved 
(from Abbott Laboratories, and Hoffmann-La Roche).

Indinavir has been studied in more than 2,000 people. It was 
approved under the FDA's accelerated approval regulations, 
based on 24-week studies which showed improvements in markers 
of HIV disease progression -- large viral load decreases, and 
CD4 count improvements -- especially when indinavir was used 
in combination with other antiretrovirals. Long-term studies 
are now ongoing to test the effect of indinavir in preventing 
clinical progression of HIV disease.

The package insert includes extensive prescribing 
information, lists of possible side effects, and key clinical 
trial results. "Crixivan must be taken at intervals of 8 
hours. For optimal absorption, Crixivan should be 
administered without food but with water one hour before or 
two hours after a meal. Alternatively, Crixivan may be 
administered with other liquids such as skim milk, juice, 
coffee, or tea, or with a light meal, e.g. dry toast with 
jelly, juice, and coffee with skim milk and sugar; or corn 
flakes, skim milk and sugar.... To insure adequate hydration, 
it is recommended that the patient drink at least 1.5 liters 
(approximately 48 ounces) of liquids during the course of 24 
hours." Administration with grapefruit juice *decreased* 
blood levels of Crixivan in one test. The dose of Crixivan is 
the same whether it is used alone, or with other 
antiretrovirals -- but the package insert should be checked 
for instructions on combination use, e.g. with ddI. A number 
of warnings and precautions, including interactions and 
incompatibilities with several other drugs, are also listed 
in the package insert.

It is important to take the full dose consistently as 
prescribed -- without reducing the dose, skipping doses, or 
taking "drug holidays." But if a dose is missed, do not 
double the next dose. In case of nephrolithiasis (kidney 
stones or related symptoms, which have occurred in about 4% 
of patients taking indinavir), a short drug interruption may 
be considered.

For information on obtaining Crixivan, and on Merck's 
reimbursement assistance program which is called SUPPORT(TM), 
patients and physicians can call 800/927-8888, beginning 
March 18.

Note: At this time, the impression among treatment advocates 
is that overall, Merck's indinavir seems to be the best 
choice of the three protease inhibitors now approved. Still, 
those who can wait to start protease inhibitors may want to 
wait until more is known about how to use them in the best 
combination regimens to minimize viral resistance (which 
seems to be more of a problem with the Merck and Abbott drugs 
than it is with saquinavir, the Roche protease inhibitor). 
But those who do want to start indinavir within the next six 
to 12 months should know that there will be a limited supply 
of this drug over the next several months (depending on U.S. 
and international demand) -- and that those who seek indinavir 
immediately may have the best chance to obtain it. Any supply 
problem should end around autumn of this year, when new 
manufacturing facilities are scheduled to begin production. 
(We do not expect any shortage of the Roche or Abbott 
protease inhibitors.)

Since it is medically inadvisable to start indinavir and then 
discontinue (as that would encourage the development of 
resistant viruses, reducing future usefulness of this and 
certain other protease inhibitors), Merck is setting up a 
system to track prescriptions in order to make sure that 
refills are available for all who start using the drug. 
Current plans are to accept new patients into this system on 
a first-come-first-served basis.

If you expect to need indinavir in the near future, check 
with your physician now about getting it. But if you can 
wait, the supply and distribution problems should be over 
within a year -- and the drug may be more useful then than it 
would be now, since physicians will know more about how best 
to use it.


***** Ritonavir (NORVIR(TM)), Abbott Protease Inhibitor, Approved

With record speed, ritonavir (Norvir(TM)), Abbott 
Laboratories' protease inhibitor, was approved by the FDA on 
March 1, 1996 (one day after approval was recommended by the 
FDA's Antiviral Drugs Advisory Committee) -- and was for sale 
in some pharmacies within a week. For more information on the 
debates at the advisory meeting which recommended this 
approval, see "Protease Inhibitors at FDA Advisory Hearings," 
below.

Ritonavir is the only protease inhibitor which already has 
proven survival benefit (the others might work just as well, 
since they have comparable effects on viral load and CD4 
counts, but they have not completed their clinical-endpoint 
trials yet, so no data on survival are available). But 
ritonavir has also raised more safety concerns than the 
others. It has strong interactions with many drugs used by 
persons with HIV; it should not be used concurrently with at 
least 22 of them, and requires dose reduction and/or 
monitoring with some others. Patients taking other 
medications must consult with their physicians before 
starting ritonavir. Abbott has prepared physician and patient 
instructions regarding potential drug interactions. 

Other concerns are that ritonavir has little safety data 
beyond six months at this time. It strongly inhibits a 
specific liver enzyme, which presumably is in the body for a 
reason; blocking this enzyme for extended periods might cause 
problems. And we have heard more anecdotal reports of side 
effects with ritonavir than with the other protease 
inhibitors.

There is also the problem of resistance and cross resistance 
(especially cross resistance to Merck's Crixivan); this may 
be minimized by optimal use of the drug -- by combining it 
with two or more other antivirals, and by not missing doses 
or taking "drug holidays."

It is likely that many people who could afford to wait a few 
months or more before starting protease inhibitors may choose 
to do so. By that time, the Merck drug will also be 
available; and physicians will know more about which drugs to 
choose and how to make best use of them. Combinations may 
work best when a patient starts all the drugs in that 
combination at about the same time, without extensive prior 
use of any of them.

For those considering starting ritonavir now, we note some 
information from the package insert (the FDA-approved 
prescribing information for physicians). This document will 
be published in the PHYSICIAN'S DESK REFERENCE; meanwhile, 
patients may be able to get a copy from their pharmacist or 
physician.

Administration

Ritonavir is sold in two forms, capsules and oral solution. 
It should be taken with meals if possible.

"The recommended dosage of ritonavir is 600 mg twice daily by 
mouth. Some patients experience nausea upon initiation of 600 
mg b.i.d. dosing; dose escalation may provide some relief: 
300 mg b.i.d. for 1 day, 400 mg b.i.d. for 2 days, 500 mg 
b.i.d. for 1 day, and then 600 mg b.i.d. thereafter. In 
addition, patients initiating combination regimens with 
NORVIR and nucleosides may improve gastrointestinal tolerance 
by initiating NORVIR alone and subsequently adding 
nucleosides before completing two weeks of NORVIR 
monotherapy."

"Patients should be informed to take ritonavir every day as 
prescribed. Patients should not alter the dose or discontinue 
ritonavir without consulting their doctor. If a dose is 
missed, patients should take the next dose as soon as 
possible. However, if a dose is skipped, the patients should 
not double the next dose."

There is no children's dose, as there have been no studies of 
safety or effectiveness in children. 

Drug Interactions

The package insert begins with a warning box: "Co-
administration of NORVIR with certain nonsedating 
antihistamines, sedative hypnotics, or anti-arrhythmics may 
result in potentially serious and/or life-threatening adverse 
events due to possible effects of NORVIR on the hepatic 
metabolism of certain drugs. See Contraindications and 
Precautions sections." Later text includes cautions and 
warnings about other kinds of drugs as well.

The warnings about drug interactions are too extensive to 
reproduce here. Patients and physicians should note that they 
appear in different sections of the package insert, including 
Special Populations -- drug-drug interactions; 
Contraindications; and Precautions -- drug interactions.

Tobacco use has been found to decrease ritonavir blood levels 
by 18 percent.

Adverse Events

After about three months of use of the drug in clinical 
trials, "the most frequently reported clinical adverse 
events, other than asthenia [lack of strength, fatigue], 
among patients receiving NORVIR were gastrointestinal and 
neurological disturbances including nausea, diarrhea, 
vomiting, anorexia [loss of appetite], abdominal pain, taste 
perversion, and circumoral and peripheral paresthesias 
[abnormal sensation]." Tables showing percentages of patients 
with dozens of other clinical and laboratory abnormalities 
which might be drug related are included in the package 
insert.

Because ritonavir can cause changes in some laboratory tests, 
certain testing should be done to establish a baseline before 
the drug is started. The testing should be repeated 
periodically during therapy, or if symptoms occur, to monitor 
for possible problems.

"Ritonavir pharmacokinetics have not been studied in patients 
with hepatic insufficiency." However, some patients with 
hepatitis have been included in the clinical trials of the 
drug.

Cost and Reimbursement

Ritonavir is the most expensive antiretroviral; Abbott's 
charge to wholesalers is $6500 per year. We could not get the 
"average wholesale price" (the price which wholesalers charge 
pharmacies) by press time. We found some confusion about 
retail prices; patients should check several pharmacies, 
including mail-order or other large pharmacies serving many 
persons with HIV, before making major purchasing decisions.

"NORVIR is indicated in combination with nucleoside analogues 
or as monotherapy for the treatment of HIV infection when 
therapy is warranted." This official language from the 
package insert should help in getting reimbursement from 
insurance companies which use FDA approval as the basis for 
their reimbursement decisions, as there are no CD4 or other 
stated limits for use of ritonavir. But many managed-care 
systems use their own formularies which do not include all 
FDA-approved drugs, so the FDA's approval language may matter 
less with them.

Because interrupting therapy can make one more likely to 
develop virus resistant to this and some other protease 
inhibitors, persons should avoid starting either ritonavir or 
indinavir unless they expect to be able to continue without 
interruptions.

For assistance in getting reimbursement for ritonavir, call 
800/659-9050.


***** Protease Inhibitors at FDA Advisory Hearings

by John S. James

[Note: This writer was unable to attend the recent meetings 
of the FDA advisory committees, due to the flu. AIDS 
treatment writer Mark Mascolini helped with the research for 
our coverage of the protease inhibitor and nucleoside analog 
combination meetings.]

On February 28-March 1, four separate one-day meetings of FDA 
advisory committees took place at two different sites near 
Washington, D.C.

FDA advisory committees consist of outside experts (not FDA 
employees) who meet when requested and advise the FDA on drug 
approvals and related issues. While the FDA does not have to 
follow the recommendations of the committees, it almost 
always does. These meetings are important because they 
usually present more information and analysis about a 
potential new treatment than is available from any other 
public source. (Most FDA advisory committee meetings are open 
to the public, at least in large part, although sometimes 
closed sessions are scheduled to review confidential 
proprietary data.)

The Antiviral Drugs Advisory Committee, which reviews most 
AIDS drugs seeking marketing approval, held three of the 
hearings -- on recommendations for indinavir (Crixivan(R), 
Merck's protease inhibitor); ritonavir (NORVIR(TM), Abbott's 
protease inhibitor); and also on usage of AZT/ddI/ddC, in 
view of new data from major clinical trials. Also, the 
Endocrine and Metabolic Drugs Committee met separately (at 
the same time as the indinavir hearing) to review the request 
for approval for human growth hormone to treat AIDS-related 
wasting. This article reviews the hearings on the two 
protease inhibitors; the human growth hormone hearing is 
examined in a separate article, below, and the meeting on new 
recommendations for use of the older drugs will be covered in 
a later issue of AIDS TREATMENT NEWS.

Indinavir (Crixivan) -- Merck's Protease Inhibitor

The March 1 indinavir hearing was the smoothest of the four 
meetings, mainly because Merck & Co. had the data and trials 
it needed to support the recommendation it was asking for.

Merck was seeking (and has now been granted) clearance to 
market indinavir under the FDA's "accelerated approval" 
regulations. Accelerated approval allows an HIV treatment to 
be approved based on CD4 count and viral load improvements in 
clinical trials -- provided that larger trials are in place to 
also prove clinical benefit to patients, such as longer 
survival or fewer opportunistic infections. 

About 2,000 volunteers have now taken indinavir at the 
currently accepted dose (800 mg every 8 hours); 600 have 
taken this dose for at least six months, and 250 for at least 
a year. The main safety concerns have been an increase in 
bilirubin (but without evidence of liver toxicity), and 
kidney stones or related symptoms in less than three percent 
of patients. The most common (but less serious) side effects 
are rash, dry skin, and altered sense of taste.

Merck reported results of several trials, and they are 
consistent with what was known before. More information on 
specific trial results (some of which were never presented 
publicly before this meeting) is available through NATAP, the 
National AIDS Treatment Advocacy Project; for contact 
information, see "FDA Hearings: For More Information," below.

While drug interactions are much less of a problem with 
indinavir than with ritonavir, indinavir does have important 
interactions several other drugs. Dose adjustments are 
required in some cases; other drugs cannot be used at all 
with indinavir.

At the end of the day, the Committee recommended accelerated 
approval for indinavir -- recommending combination treatment 
when possible, but with an option for indinavir alone for 
people who cannot tolerate the nucleoside analogs.

Ritonavir (NORVIR) -- Abbott's Protease Inhibitor

The February 29 meeting on ritonavir was more difficult than 
the indinavir meeting. It was followed by a private late-
night meeting between Abbott and the FDA, during which final 
agreements were negotiated. On the following day, Abbott 
distributed a letter announcing that it would conduct trials 
to provide certain additional data; and the FDA announced 
that ritonavir would be approved.

The reason the Committee meeting was difficult is that while 
Abbott came in with the best results so far for any HIV 
treatment -- clear evidence that the drug substantially 
reduced the risk of death and of opportunistic infections in 
a major trial -- other important information was unavailable. 
For example, there is little information on safety or 
efficacy beyond six months, which is especially worrisome for 
a drug with important safety concerns. There are no pediatric 
data. Information is inadequate on how well the drug works in 
people with earlier stages of HIV infection (the trial which 
showed clinical benefit was only open to those with CD4 
counts under 100).

There were many different ideas on the Committee, and much 
discussion, about what proof was needed for efficacy in 
earlier disease. The issue is that the accelerated approval 
regulations require subsequent trials that show direct 
clinical benefit to patients, to eventually back up the early 
approval which is based on improvements shown in blood tests, 
like CD4 count and viral load. But it has always been very 
difficult -- and is now almost impossible -- to prove delayed 
disease progression in persons with high CD4 counts, because 
it will take many years for enough volunteers to get sick to 
provide statistical proof of benefit, and people are 
unwilling to stay on the same treatment that long while 
better treatments are becoming available. (The proposed 
"symptom reduction trials" to get around this problem -- see 
AIDS TREATMENT NEWS #228, #229, and #231 -- have not caught on 
at this time, probably because while they could provide 
clinical proof of benefit quickly, they would not provide 
long-term balance of risks and benefits, especially for 
asymptomatic patients.)

The compromise that seemed to win wide acceptance at the FDA 
advisory meeting was a long-term surrogate marker (CD4 and 
viral load) and safety study, which would use the clinical 
endpoints of illness and survival primarily to assure safety, 
while using CD4 and viral load changes to test for durability 
of response to the drug. The private meeting that evening 
built on this idea, with Abbott agreeing to "provide long-
term follow-up safety and clinical endpoint data from ongoing 
studies M94-247 and M94-245 to assess the comparative 
clinical efficacy and safety data in patients with advanced 
stage disease versus patients with early stage disease." 
Also, Abbott agreed "to provide data from a study in patients 
with higher CD4 cell counts (>100 cells/microliter) looking 
for durability of response by evaluating CD4 response, HIV 
RNA response and safety from a study comparing ritonavir to 
ritonavir+saquinavir." And Abbott agreed "to participate in a 
clinical study to define the safety and clinical efficacy of 
ritonavir in pediatric patients."

With these agreements in place, the FDA sent Abbott an 
approval letter "for the use of ritonavir in combination with 
nucleoside analogs or as monotherapy for treatment of HIV 
infection when therapy is warranted." The labeling 
(information for physicians) will describe the evidence on 
which the approval is based, and the limitations of this 
evidence for late-stage and also for early-stage HIV disease.

Ritonavir Comment

The key issue for the Committee seems to have been the 
balancing of risks and benefits in early disease, especially 
because the drug has important safety issues and no long-term 
safety data. The resolution which resulted left physicians 
and patients with maximum flexibility in the use of this 
drug. We believe this decision was the right one -- but that 
the success of this drug will depend on Abbott's ability to 
educate physicians, pharmacists, and patients on how to use 
ritonavir correctly, and on the company's continued ability 
to rapidly conduct the research on which this education must 
be based.


***** FDA Antiviral Hearings: Community Perspectives

Dave Gilden, Gay Men's Health Crisis:

[Since we did could not attend the FDA's Antiviral Drugs 
Advisory Committee hearings, we asked people who did attend 
to comment on drafts of our report. Dave Gilden, editor of 
TREATMENT ISSUES, sent us the following, which we found 
insightful and important enough to quote in full, with his 
permission.]

Gilden: "My sense about the FDA is that the people there have 
become convinced that a four drug combination will be highly 
effective in suppressing HIV. Researchers like David Ho are 
arguing that three drugs will provide long-term viral 
suppression but that you need four drugs to insure that there 
is no pre-treatment mutant HIV able to resist the entire drug 
combination -- or to prevent eventual emergence of such virus.

"The FDA is therefore determined to push the necessary drugs 
through the approval process, whether the data on each one is 
complete or not. The other issue affecting the FDA 
deliberations is the FDA reform movement in Congress, which 
the FDA is countering in part by showing how decisively it 
can act when the situation calls for rapid drug approvals.

"Therefore, I watched the spectacle of ritonavir getting the 
kid glove treatment from FDA reviewers, and David Kessler 
pushing for full approval, while I saw Serono and human 
growth hormone get positively torn apart the next day. We can 
expect easy treatment for nevirapine and delavirdine too, 
even though the available data on these drugs' benefits is 
weak indeed. These two non-nucleoside reverse transcriptase 
inhibitors will then be the fourth drugs in the four-drug 
regimens, along with one or two nucleoside analogs [e.g., AZT 
plus 3TC, or ddI] and one or two protease inhibitors. Viral 
load testing, central to optimizing and periodically 
adjusting the four-drug regimens in each person, now seem to 
be on the FDA fast track, too. (The Hoffmann-La Roche PCR 
test will be considered by the Blood Products Advisory 
Committee on March 21.)

"Speaking of using two protease inhibitors, the upcoming 
ritonavir/saquinavir trial assumes tremendous importance in 
this four-drug scenario. I would put more money on using two 
protease inhibitors, especially if there is little cross-
resistance, than adding a non-nucleoside reverse 
transcriptase inhibitor. Saquinavir is extremely potent in 
laboratory tests, and ritonavir may rescue its disappointing 
performance in the body. [Caution -- these drugs will require 
extreme dose adjustment when combined, and *must not* be used 
together until safe doses are known. Near-fatal side effects 
have occurred from combining protease inhibitors 
inappropriately. JSJ]

"In the meantime, the most treatment-savvy PWA I know is 
arguing that Merck's indinavir looks better than ritonavir, 
from the available data, and that we should not be swayed by 
ritonavir's full approval for advanced disease. He is not 
alone in this opinion. The arguments favoring indinavir are: 
better safety (though neither compound has much long-term 
data), better patient compliance with the recommended regimen 
(important to avoid breakthrough drug-resistant HIV), fewer 
evident drug-drug interactions, better CNS (central nervous 
system) penetration, data indicating activity in lymph nodes, 
and indications of greater durability of antiviral response 
(at least as monotherapy). Abbott also has a much worse 
record of working with the community, and the chances are 
weak of the company now trying to fill the tremendous gaps in 
our knowledge of how to use protease inhibitors. In 
particular, we need to know how well the individual brands 
work over the long run, when best to start protease 
inhibitors (which is highly influenced by the durability of 
response issue), and what to follow these compounds with 
should they start to fail."

[TREATMENT ISSUES, "the Gay Men's Health Crisis newsletter of 
experimental AIDS therapies," is published monthly; annual 
subscriptions are available for a suggested contribution of 
$35 for individuals, $70 for physicians, institutions, or 
international subscriptions; a full set of back issues is 
available for $25. Make checks payable to GMHC, and mail to: 
GMHC, Treatment Education, 129 West 20th Street, 2nd floor, 
New York, NY 10011.]

Martin Delaney, Project Inform:

[The following are from a February 29 press release by 
Project Inform, supporting accelerated approval of ritonavir, 
but expressing caution about how the drug should be used.]

Delaney: "While this [improved survival] outcome is 
significant, it overlooks two other important facts from the 
study. It is our understanding that the majority of the 
deaths reported in this data occurred within the first six 
weeks of treatment, raising questions as to whether the 
outcome reflects the true longer-term effect of the drug. 
More importantly, we are very concerned that the data shows a 
rapid loss of antiviral activity, probably due to the 
development of drug resistance, within six months when used 
in this fashion. Since resistance to this drug confers 
resistance to most other protease inhibitors, there is good 
reason to fear that such a use of the drug may lead only to 
short-term benefit followed quickly by long-term multi-drug 
cross resistance to many of the key products in the field of 
protease inhibitors. There is evidence that the drug can work 
far better when used properly; giving too much weight to this 
data may promote use of the drug in this suboptimal fashion."

"We think it is critical that Abbott make clear to physicians 
and patients that great care should be employed in how these 
drugs are used. Simply adding them without thought to 
existing therapy is unlikely to produce a lasting benefit, 
while running a large risk of creating multi-drug cross 
resistant strains of virus."

A position paper available through the Project Inform hotline 
(800/822-7422, 10 a.m. to 4 p.m. Pacific time Monday through 
Saturday) describes these concerns in greater detail, and 
provides guidelines for the optimal use of protease 
inhibitors, based on what is known today. It will be 
published in the April 1996 issue of PI PERSPECTIVE.


***** FDA Hearings: For More Information

The most authoritative information about each of the three 
protease inhibitors now approved is the package insert for 
each drug. Incidentally, Merck is planning to work with the 
FDA to develop a patient's version of the package insert for 
indinavir.

Later, a full transcript and also a summary of each advisory 
committee hearing will be available from the FDA.

Probably the most in-depth public information at this time 
about the protease inhibitors is available through Jules 
Levin's National AIDS Treatment Advocacy Project; it includes 
a review of each clinical trial of the drugs, and the 
resulting data. If you have a World Wide Web browser, you can 
receive it immediately at http://www.aidsnyc.org/natap. Jules 
can also be reached by email at JuLev@aol.com, or day or 
evening by phone at 718/624-8541 or by fax at 718/624-8399. 
His mailing address is NATAP, 72 Orange Street, Brooklyn, NY 
11201.

In addition to information from these recent hearings, NATAP 
also has a 45-page booklet on the five protease inhibitors 
likely to be the first available -- saquinavir (Roche), 
ritonavir (Abbott), indinavir (Merck), nelfinavir (Agouron), 
and VX478 (Vertex / Glaxo Wellcome). Also available is a 4-
hour videotape of NATAP's community forum on protease 
inhibitors, January 6, 1996, in New York.

Note: As this issue went to press, NATAP announced a free 
community forum on protease inhibitors in Los Angeles, April 
13, 1996, from 1:00 p.m. to 4:40 p.m. in the Paramount 
Theater, 5555 Melrose Ave. (enter at Bronson St. gate). This 
event is also sponsored by Kraus Medical Partners, and Being 
Alive -- and co-sponsored by 17 other AIDS organizations. For 
reservations, call 800/238-7828, ext. 8145. For more 
information, contact NATAP at the above computer addresses, 
fax number, or phone number.


***** Human Growth Hormone Not Recommended for Approval on 
Narrow Advisory Panel Vote

by John S. James

On March 1, the FDA's Endocrinologic and Metabolic Drugs 
Advisory Committee, meeting with outside experts including 
some members of the Antiviral Drugs Advisory Committee, voted 
not to recommend approval for AIDS-related wasting for 
Serostim(TM), the recombinant human growth hormone produced 
by Serono Laboratories, Inc. The vote was eight opposed and 
seven in favor.

According to Bill Thorne from ACT UP/Golden Gate, who was the 
non-voting community representative on the panel and had gone 
to the hearing hoping the drug would be approved, some of 
those who voted no believe that growth hormone does work for 
the requested indication, but were very disappointed with the 
data presented by the company. He said the Committee clearly 
wanted to vote for accelerated approval -- which would have 
approved the drug for marketing, but required the company to 
do additional research -- but that the FDA asked the Committee 
not to vote on accelerated approval, since the company had 
not filed for it. Many physicians are dissatisfied with the 
outcome; they know growth hormone works for some patients, 
and want to be able to use it. (The drug is currently 
available through a pre-approval "treatment IND" expanded 
access program, but the paperwork for this program is 
difficult.)

What were some of the concerns about the data?

* Committee members feared that the dose requested might be 
too high. An FDA analyst said that the dose being sought was 
twice as high as that used in treating any other condition, 
and that this dose was not justified by data. Committee 
members were concerned, since human growth hormone can cause 
irreversible side effects. (Serono told us that all the other 
dosage information was in children, who often use growth 
hormone for many years -- and that no irreversible side 
effects occurred in Serono's trials.)

We have been told that Serono tried to present data showing 
that lower doses were inadequate, but the Committee did not 
allow it to do so. According to Bill Thorne, Serono did not 
seem to understand the procedure of the hearing. In the 
morning, Serono presented its data (which had also been given 
to members in a binder before the meeting). Then an FDA 
analyst critiqued Serono's presentation. In the afternoon, 
the Committee deliberated and then voted. Serono tried to 
interject at that time, but was told that during the 
Committee deliberations it could only respond to questions. 
It was not allowed to pull out bits and pieces when that 
suited its interests, after the FDA's critique. (Serono told 
us that it had 60 minutes to present 40,000 pages of their 
NDA -- new-drug application for marketing approval -- and that 
in other hearings, advisory committees often allow companies 
to address questions that arise, but this one did not. 
According to Serono, they brought thousands of slides and 
could easily have cleared up many of the questions.)

[Although not part of the hearing, other dosage issues were 
raised in the December 1995 issue of MEDIBOLICS, a newsletter 
on anabolic steroids and related medical treatments published 
by Michael Mooney in West Hollywood, California. One article 
indicated that Serostim appears to be deliberately formulated 
to prevent people from using lower doses without throwing 
some of the product away -- that Serostim, packaged in 6 mg 
vials, is "designed to be used within 24 hours after mixing, 
when every other growth hormone product in the world, 
including (Serono's) own product sold in Italy, called 
Saizen, is made to last 14 days." The difference is that 
Serostim left out an inexpensive preservative, meta-cresol, 
and therefore could have dangerous bacterial growth if kept 
over 24 hours after mixing. The article quoted an AIDS 
patient in San Francisco who had "constant excruciating joint 
pain and random outbreaks of oil-filled cysts on my face and 
upper body" using 6 mg either every day or every other day, 
until learning about the dosage controversy and reducing the 
dose, which required him to throw part of each vial away.

Another article speculated that the oral anabolic steroid 
oxandrolone (Oxandrin(R)) might work as well or better than 
growth hormone at considerably less cost -- even though it 
also is overpriced. Trials of oxandrolone should be finished 
later this year. The article also mentions injectable 
anabolics which might be very low cost alternatives for some 
patients -- testosterone cypionate for $8 per month, or 
nandrolone decanoate for $32 per month. (A third article in 
the same issue criticizes physicians who charge $45 to $60 
for each injection, when patients who are paying out of 
pocket could inject themselves at home.)

MEDIBOLICS is published four times a year for $15 U.S., $22 
Canada and elsewhere, P.O. Box 333, 836 N. La Cienega 
Boulevard, West Hollywood, CA 90069, fax 310/659-1597, email 
mmooney@a.crl.com.]

* Serono has provided Serostim to close to 900 people in its 
pre-approval treatment IND program (which charges for cost 
recovery, as allowed under the treatment IND regulations, 
although as many as 30% of the patients have received drug 
without charge through the company's indigent patient 
assistance). Usually such expanded-access programs provide 
important data on safety, toxicity, and the frequency of dose 
reductions due to side effects. Yet Serono never mentioned 
this experience in its presentation to the Committee -- even 
when directly asked by Sandra Hernandez, M.D., head of the 
San Francisco Department of Public Health, who served on the 
Committee. (Serono told us that they did not present this 
treatment IND data because it was not part of their NDA 
application, due to the timing of when the NDA was filed.)

* There is little information on long-term safety and 
toxicity, beyond 12 weeks -- although patients clearly need to 
use growth hormone for longer than that. (Serono told us 
that, of 259 volunteers enrolled in its long-term study, more 
than 40% were on the drug for more than six months, and about 
5% were on drug for two years or more.)

* In one of the major trials presented to the Committee, 
there were actually more deaths in the treatment than in the 
placebo group. Apparently this difference was not 
statistically significant (meaning that it might have 
resulted from chance); still it is disconcerting, and 
emphasizes the need for long-term data. (Serono told us that 
there were similar numbers of deaths for people while on 
study -- that most of the deaths the Committee was discussing 
occurred off study. In almost all cases, these people had 
been off growth hormone treatment for at least three months. 
Serono will continue long-term followup.)

* The Committee wondered if there is a target population that 
can be identified that is likely to respond well to human 
growth hormone. Or is this a treatment to use in the hope 
that it will work in some percentage of the cases?

* Is the once-daily scheduling best? Or could the drug be 
taken less often?

Cost

Growth hormone at the Serono dose is expected to cost between 
$50,000 and $100,000 per year (Serono has not announced a 
price yet); its "cost recovery" for the treatment IND program 
charged $25 per milligram, slightly more than $50,000 per 
year for the 6 mg per day the company recommends, and the 
price of the approved drug will be higher than that. Serono 
has said that its recombinant human growth hormone, made from 
mammalian cells, is much more expensive to produce that other 
recombinant human growth hormone, made from E. coli. We have 
no way to evaluate this claim. We do not know how much 
difference the mammalian cell derivation makes, since the E. 
coli version does promote human growth over long periods of 
time.

The price of human growth hormone (at least the E. coli 
version) appears to be almost all profit, since a quite 
similar product to increase milk production in cows costs 
about two thousand times less. AIDS TREATMENT NEWS is trying 
to learn why the international price has stayed so high for 
so long, since recombinant human growth hormone is produced 
by independent companies, and competition would normally have 
led to price reductions. Incidentally, we have heard warnings 
about "underground" human growth hormone from Eastern Europe, 
which is not recombinant but prepared from cadavers, and 
could carry a fatal brain infection.

Negotiations

Bill Thorne, who has been involved in three-way negotiations 
between Serono, the FDA, and community activists, sees Serono 
as "attempting to contain whatever commitment they have in 
the future [by holding out for traditional approval]. And now 
the FDA is coming to doubt Serono as a source of data on its 
own product, and becoming reluctant to give even accelerated 
approval. The FDA does have the legal authority to grant 
accelerated approval even without being asked by the sponsor, 
although it is very reluctant to do so. 

"We need to push the FDA to take charge of this situation and 
do what is right for patients -- meaning to grant accelerated 
approval, whether Serono requests it or not. Activists agree 
that the drug does work, and has been used in other patients 
for years without any side effect so frightening we cannot 
manage it, in comparison with the dangers of wasting 
syndrome, which is causing many preventable deaths."

Jeff Getty, also of ACT UP/Golden Gate, is trying to 
negotiate a $25,000 cap per year per patient. He has told 
Serono that without the cap, activists will oppose Serono's 
efforts to get traditional (vs. accelerated) approval, and 
also its effort to get orphan drug status which would lock in 
its monopoly for seven years.

Gina Cella of Serono told AIDS TREATMENT NEWS, "Everyone 
agrees that Serostim should not be denied approval; we are 
all working toward that end. We are in active discussion with 
the FDA; we are pleased to have the opportunity to continue 
discussions with them, to respond to their questions and 
present additional data as requested. We are committed to 
obtaining approval for Serostim in some form, full or 
accelerated approval. We are also committed to continuing 
research in AIDS wasting and the use of Serostim, and will 
continue additional study."

For more information on the negotiations around human growth 
hormone approval, contact ACT Up/Golden Gate, 415/252-9200, 
fax 415/252-9277.

Comment

To understand what happened it is necessary to look at it 
from several different points of view:

* One expert physician may have summarized the views of many 
by commenting that human growth hormone does something 
important which no other drug does -- and that used to be 
enough for approval (implying that it should still be enough 
for approval in this case). He sees Serono as very good in 
certain other areas, but inexperienced regarding its 
presentation to this Committee.

* Most of the Committee may have agreed with that view of the 
drug, in their hearts -- but their job was to decide if that 
case was proven by the data placed before them, and a slim 
majority could not agree that it had been proven.

* The company believes that it has the data needed to clear 
up some of the Committee's concerns -- but could not include 
everything in its one hour presentation, and later was not 
allowed to address other concerns after they came up.

* The FDA insists that accelerated approval must not become a 
safety net for drugs which fail to achieve traditional 
approval. (Otherwise the usefulness of accelerated approval 
could be destroyed, as payers would consider it second rate 
and refuse to reimburse.)

Hopefully the company will be able to resolve enough of the 
remaining issues to show the FDA's staff that Serostim can 
qualify for some form of approval.


***** Consensus Statement on the Further Development of 
Protease Inhibitors And Human Growth Hormone

[The following consensus statement is an excellent summary of 
what is needed today in AIDS treatment research. It also 
reflects new common ground, after the long-running, so-called 
"East Coast/West Coast" disputes among AIDS treatment 
activists (over whether to emphasize better "answers" through 
more rigorous clinical trials, or faster "access" to new 
treatments by patients and physicians). David Barr of Gay 
Men's Health Crisis and Martin Delaney of Project Inform 
organized and led the meeting that developed this statement. 
JSJ]

We, the undersigned individuals and organizations, represent 
hundreds of thousands of people with HIV infection in the 
United States. We are excited and hopeful that the therapies 
being reviewed for approval this week (two protease 
inhibitors and human growth hormone) can provide a 
substantial benefit for people with HIV. However, approval of 
these products is not the end of the process of drug 
development. In order to provide real access and information 
about how to use these drugs safely and effectively, we call 
on the Food and Drug Administration, the National Institutes 
of Health and the pharmaceutical industry and third-party 
payers to meet the demands outlined below. Failure to do so 
will seriously undermine the value that these therapies will 
offer to patients today and in the future.

1) Approve both indinavir and ritonavir for people with HIV 
infection for whom anti-viral treatment is indicated based on 
immunologic, clinical and biological markers. Approve human 
growth hormone for the treatment of wasting syndrome. 

2) Whatever regulatory mechanism is used for approval, 
industry and government must agree to engage in post-
marketing research to answer key unanswered questions about 
safety and efficacy. In order for this research to be 
effective, it will require a collaborative effort between 
industry, government, academia and community heretofore 
unseen in AIDS research. The commitment to engage in this 
effort quickly should be of paramount importance. We insist 
that a strategic plan be presented for achieving these goals 
by the time of the 11th International Conference on AIDS, to 
be held in Vancouver in June, 1996. 

3) The following is a list of questions that we agree must be 
answered as soon as possible. The list is not meant to be 
exhaustive, but rather to highlight those issues we believe 
are of highest priority: 

* When in the course of HIV disease should anti-viral 
treatment generally be initiated? * Which treatment regimens 
should be used as initial therapy? * What are the best 
strategies for using combinations of anti-viral drugs, 
including protease inhibitors, for nucleoside-experienced 
patients? * When should people switch or stop anti-viral 
treatment regimens * What is the pharmacokinetic and long-
term safety profile on protease inhibitors? * To what level 
must viral load be reduced and sustained to successfully halt 
disease progression? * How will pediatric formulations of 
protease inhibitors be developed and studied? * What is the 
effect of protease inhibitors on perinatal transmission? * 
What is the optimal dose of human growth hormone, alone or in 
combinations? 

4) Approve viral load test kits for clinical management now, 
not in six months. This is essential if we are going to be 
able to use these treatments effectively. 

5) Provide protease drugs and growth hormone, at no cost, to 
all former and current clinical trial and expanded access 
program participants and collect long-term safety data from 
this group. This would provide the easiest and fastest way to 
get such information. 

6) Promotional and educational materials must be developed 
and made available to doctors, patients, pharmacists and 
health educators immediately to inform them about safe and 
effective use of these products particularly around issues of 
compliance with treatment regimens and drug interaction 
problems. Community and consumer input into the development 
and distribution of such materials is essential.

7) Reimbursement decisions should be driven by clinical 
and/or surrogate data from controlled clinical studies. 

8) Prices for these drugs must be fair, reasonable and 
sensitive to the current crisis in health care funding. Each 
company must guarantee treatments to those who have no other 
means of access or less than full coverage through patient 
assistance programs. 

9) At minimum, pharmaceutical companies must agree to provide 
AIDS Drug Assistance Programs with similar rebates that are 
given to Medicaid programs.

[Over 30 organizations have already signed this statement, 
including AIDS Action Council, AIDS Research Alliance, AIDS 
Treatment News, American Foundation for AIDS Research, Center 
for AIDS Prevention Studies, Critical Path AIDS Project, Gay 
Men's Health Crisis, Healing Alternatives Foundation, 
National Association of People with AIDS, Pediatric AIDS 
Foundation, Project Inform, PWA Health Group, San Francisco 
AIDS Foundation, and Treatment Action Group.

Organizations can sign by contacting Ben Cheng or Brenda Lein 
at Project Inform, 415/558-8669 ext. 221 or 214, or David 
Barr at GMHC, 212/337-1904.]


***** AIDS and Alternative Medicine, Seattle, April 28

Bastyr University and the Bastyr University AIDS Research 
Center will present AIDS and Alternative Medicine: Current 
State of the Science, a continuing education program for 
medical practitioners and researchers. This one-day program 
will be held in Seattle on April 28 at the Washington State 
Convention and Trade Center, 800 Convention Place, Seattle, 
WA 98101.

Speakers include Lark Lands, Ph.D., John S. James, Candace 
Pert, Ph.D., Leanna Standish, N.D., Ph.D., and others.

Registration is $125 for practitioners, $75 for students; 
there is a $10 discount if paid by April 12. For more 
information about registration, including continuing 
education credit, call Bastyr University's Department of 
Continuing Education, 206/517-3577.


***** AIDS TREATMENT NEWS
      Published twice monthly

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   Internet: aidsnews@aidsnews.org
Editor and Publisher:
   John S. James
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Statement of Purpose:
AIDS TREATMENT NEWS reports on experimental and 
standard treatments, especially those available now. We 
interview physicians, scientists, other health 
professionals, and persons with AIDS or HIV; we also 
collect information from meetings and conferences, 
medical journals, and computer databases. Long-term 
survivors have usually tried many different treatments, 
and found combinations which work for them. AIDS 
Treatment News does not recommend particular 
therapies, but seeks to increase the options available.

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ISSN # 1052-4207 

Copyright 1996 by John S. James.  Permission granted for 
noncommercial reproduction, provided that our address 
and phone number are included if more than short 
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