Subject: AIDS TREATMENT NEWS #195
From: "John S. James" <[email-masked]>
Date: 19 Mar 94 14:58 PST

AIDS TREATMENT NEWS Issue #195, March 18, 1994
   phone 800/TREAT-1-2, or 415/255-0588

CONTENTS:

Kaposi's Sarcoma (KS): Angiogenesis Inhibitors in Early 
Trials

DOX-SL (Doxil) Kaposi's Sarcoma Treatment: Trials, 
Development Status

California: AIDS Drug Assistance Program, New Drugs Available 
April 1

FDA Holds Buyers' Club Drugs: Review OF Access Issues

***** Kaposi's Sarcoma (KS): Angiogenesis Inhibitors in Early 
      Trials

by Michael Marco

[Note: New York treatment activist Michael Marco heads the 
Oncology Project of the Treatment Action Group (TAG), which 
reports on treatments and research for various AIDS-related 
malignancies, and for Kaposi's sarcoma (KS). He is also co-
authoring (with Marty Majchrowicz from AIDS Project Los 
Angeles) a report on KS pathogenesis, treatments, and current 
opinions of noted clinicians and researchers.]

Angiogenesis -- the formation of new blood vessels -- takes 
place normally during wound healing. But abnormal 
angiogenesis is an important contributor to certain diseases. 
In cancer, for example, solid tumors must be able to 
stimulate the growth of new blood vessels to nourish the 
tumor cells, or they cannot grow beyond a small size. And 
evidence now suggests that Kaposi's sarcoma may not be a true 
cancer in most cases, but instead may be due to abnormal 
blood-vessel growth caused by dysregulation of angiogenesis.

Since normal growth of blood vessels is not necessary at most 
times during a person's life, researchers are developing 
drugs which inhibit angiogenesis (both normal and abnormal), 
in the hope of creating an entirely new class of treatments 
for cancer and for KS. This article outlines the current 
status of the research into three of these potential drugs, 
and describes the clinical trials which are currently open. 
(Note: For previous coverage of angiogenesis inhibitors, see 
AIDS TREATMENT NEWS issues #188, #162, #135, and #122.)

Three anti-angiogenesis compounds currently in early clinical 
trials as KS treatments are Tecogalan (SP-PG, also called DS-
4152), TNP 470 (formerly called AGM-1470), and recombinant 
human platelet factor 4 (rPF4). They have only been tested in 
a small number of patients with KS, and have mostly shown a 
lessening of KS-associated swelling, and some minor activity 
on existing lesions. Many researchers now feel that 
angiogenesis inhibitors might be most effective in preventing 
new lesions from occurring rather than affecting pre-existing 
lesions.(1) If this is true, these drugs might work best as 
maintenance therapy after systemic chemotherapy.

Tecogalan (SP-PG): Los Angeles, New York, San Antonio, San 
Francisco

Tecogalan is an angiogenesis inhibitor which has been 
isolated from the bacterium Arthrobacter. Tecogalan prevents 
a protein (called fibroblast growth factor) from binding to 
endothelial cells (the cells which line the insides of blood 
vessels) and stimulating those cells to migrate and 
reproduce. In animal tests conducted by Robert Gallo, M.D., 
and colleagues, "nude" mice (special immunodeficient mice) 
were given a form of KS by injection of human KS cells; 
Tecogalan "led to degeneration of newly formed vascular 
lesions."(2)

Four sites are currently recruiting patients for a phase I 
dose-escalating pharmacokinetic and safety trial of 
intravenous Tecogalan. Preliminary results have shown some 
activity on existing lesions, and a considerable lessening of 
edema (swelling). So far, no serious toxicities have been 
seen, except for prolonged APTT (activated partial 
thromboplastin time, which can affect the time it takes for 
blood to clot), which normalizes after the infusion.(3) Some 
patients have also noted chills and fever.

Volunteers may have any T-helper count for this trial, but 
they must have at least five cutaneous (skin) lesions, and no 
evidence of systemic visceral involvement. During the first 
dose, volunteers will be hospitalized for 24 hours for 
monitoring; later doses will be given on an outpatient basis.

This trial is being conducted at the following four sites:

* Los Angeles: Kenneth Norris Jr. Cancer Hospital/USC. 
Investigator: Parkash Gill, M.D. Contact: 213/224-6668.

* New York City: Memorial Sloan-Kettering Cancer Center. 
Investigator: Susan Krown, M.D. Contact: 212/639-7426.

* San Antonio: Cancer Therapy Research Center. Investigator: 
Gail Eckardt, M.D. Contact: 210/616-5798.

* San Francisco: San Francisco General Hospital. 
Investigator: James Kahn, M.D. Contact: 415/476-9296x84104

TNP-470: Bethesda, Boston, Chicago, Los Angeles, St. Louis

TNP-470 is a synthetic chemical analog of fumagillin, which 
is produced by a fungus. In 1990, researchers at Harvard 
Medical School found that fumagillin and TNP-470 inhibited 
angiogenesis in laboratory tests, and inhibited the growth of 
solid tumors in mice; TNP-470 was found to be less toxic and 
50 times as powerful as fumagillin.(4) Researchers at the 
U.S. National Cancer Institute also found that TNP-470 
inhibited abnormal spindle cells, which have a major role in 
the development of KS.

Animal tests showed that very large doses, given all at once, 
caused toxicity, most notably small hemorrhages in the brain, 
lungs, heart, and retinas of dogs. The drug was better 
tolerated when given as an infusion. Therefore, initial 
clinical testing used a one-hour infusion, starting at low 
doses.

In preliminary results from the phase I trial of TNP-470 in 
persons with KS, researchers at the NCI reported that the 
drug showed some activity on existing lesions (especially in 
lessening edema, or swelling), and a decrease in the 
development of new lesions. No dose-limiting toxicities were 
found.(5) 

This trial, as well as a four-site study by the AIDS Clinical 
Trials Group (ACTG), is still ongoing; both are open for 
volunteers. There is no T-helper count requirement for these 
dose-escalating trials, but patients with pulmonary KS are 
excluded from the NCI trial; the ACTG trial excludes all 
potential volunteers with symptomatic visceral KS.

Note that the NCI trial, although conducted in Bethesda, 
Maryland (near Washington, D.C.), is open to volunteers from 
throughout the country. The NCI will pay travel expenses 
(except for the first trip), and will pay a stipend toward 
living expenses while volunteers are in Bethesda. The trial 
lasts 24 weeks.

The first listing, below, is for the NCI trial. The other 
four are locations of sites for the ACTG trial.

Bethesda, Maryland: U.S. National Cancer Institute. 
Investigator: Robert Yarchoan, M.D. Contact: 301/496-8959.

Boston: Beth Israel Hospital. Investigator: Bruce Dezube, 
M.D. Contact: Beryl Chapman, 617/735-4149.

Chicago: Northwestern University Medical Center. 
Investigator: Jamie Von Roenn, M.D. Contact: 312/908-9412.

Los Angeles: Kenneth Norris Cancer Center Hospital/USC. 
Investigator: Parkash Gill, M.D. Contact: 213/224-6668.

St. Louis: Washington University School of Medicine. 
Investigator: Lee Ratner, M.D. Contact: Mary Gould, R.N., 
314/454-0058.

Recombinant Platelet Factor 4 (rPF4): Los Angeles, 
Philadelphia, San Francisco

Recombinant platelet factor 4, a genetically engineered 
version of a substance normally found in the body, has been 
found to inhibit endothelial cells in laboratory tests.(6) 
Another research group, following up this result, found that 
rPF4 also inhibited KS cells in a dose-dependent manner.(7)

In the early phase I/II (safety and preliminary efficacy) 
trial, rPF4 was injected into one lesion, while another 
lesion on the same patient was given an inactive injection as 
a control. An anti-KS effect was found in six of the 12 
patients given rPF4. The only side effect was a mild rash 
around the lesion in approximately 20 percent of the 
patients.(8)

There are three phase I/II trials of rPF4 which are currently 
open for volunteers in the U.S. They differ in how the drug 
is administered; subcutaneously in Los Angeles, 
intralesionally in Philadelphia, and intravenously in San 
Francisco. There is no requirement for T-helper count. These 
trials will last for a maximum of eight weeks.

Los Angeles: Kenneth Norris Cancer Center/USC. Investigator: 
Parkash Gill, M.D. Contact: 213/224-6668.

Philadelphia: Graduate Hospital of Philadelphia. 
Investigator: Arthur Staddon, M.D. Contact: 215/893-7520.

San Francisco: San Francisco General Hospital. Investigator: 
James Kahn, M.D. Contact: 415/476-9296 x84104.

References

1. Pluda JM, Parkinson DR, Feigal E, and Yarchoan R. 
Noncytotoxic approaches to the treatment of HIV-associated 
Kaposi's sarcoma. ONCOLOGY. December 1993; volume 7, number 
12, pages 25-33.

2. Nakamura S, Sakurada S, Salahuddin SZ, and others. 
Inhibition of development of Kaposi's sarcoma-related lesions 
by a bacterial cell wall complex. SCIENCE. 1992; volume 255, 
pages 1437-1440.

3. Gill PS, PA-C Kidane S, Tulpule A, and others. A phase 1 
study of DS-4152, a novel angiogenesis inhibitor in the 
treatment of AIDS-related Kaposi's sarcoma. E.O.R.T.C., 
Amsterdam, March 15-18, 1994.

4. Ingber D, Fujita T, Kishimoto S, and others. Synthetic 
analogues of fumagillin that inhibit angiogenesis and 
suppress tumor growth. NATURE. December 6, 1990; volume 348, 
pages 555-557.

5. Pluda JM, Wyvill K, Lietzau J, and others. A phase I trial 
of TNP-470 (AGM-1470) administered to patients with HIV-
associated Kaposi's sarcoma (KS). The First National 
Conference on Human Retroviruses and Related Infections, 
Washington, D.C., December 1993 [abstract #31].

6. Maione TE, Gray GS, Petro J, and others. Inhibition of 
angiogenesis by recombinant human platelet factor-4 and 
related peptides. SCIENCE. January 5, 1990; volume 247, pages 
77-79.

7. Miles S, Rezai A, Martinez-Maza O, and Maione TE. 
Recombinant platelet factor 4 (rPF4) and a non-heparin 
binding derivative inhibit AIDS-Kaposi sarcoma derived cell 
lines. VII International Conference on AIDS, Florence, June 
1991 [abstract # W.A.1066].

8. Kahn J, Ruiz R, Kerschmann R, and others. A phase I/II 
study of recombinant platelet factor 4 (rPF4) in patients 
with AIDS-related Kaposi's sarcoma (KS). Proceedings: Annual 
Meeting of the American Society of Clinical ONCOLOGY. 1993; 
volume 12:A4.

***** DOX-SL (Doxil) Kaposi's Sarcoma Treatment: Trials, 
      Development Status

by John S. James

DOX-SL (formerly called Doxil -- the name has been changed to 
avoid a trademark dispute in Europe) is an experimental 
treatment, now being tested for Kaposi's sarcoma and for some 
cancers, which has generated considerable interest in the 
AIDS treatment community. This article outlines what DOX-SL 
is, what trials are underway, and what needs to happen to 
make the drug more widely available (provided that the 
results of clinical trials confirm early impressions that it 
may be useful).

DOX-SL is a liposomal form of doxorubicin (also called 
Adriamycin), a cancer chemotherapy drug. Liposomes are 
microscopic spheres of lipids (fats), which can contain 
active drugs within them. The liposomes can be specially 
prepared to give the drug desired pharmacological properties 
-- especially to improve the targeting of the active 
compound, so that it is more selective in reaching the 
intended tissues in the body, to improve efficacy and reduce 
side effects.

DOX-SL consists of very small liposomes, smaller than the 
cells of the body. Each one contains about ten thousand 
molecules of doxorubicin. These liposomes have two lipid 
layers; the outer layer contains a chemical, polyethylene 
glycol (PEG), which makes the liposomes less likely to be 
destroyed by the immune system, a major problem in the early 
development of liposomal drugs.

An early phase I (dosage and toxicity) trial of DOX-SL, in 
volunteers with Kaposi's sarcoma, has found that it delivers 
about four to ten times the concentration of doxorubicin to 
the lesion as the conventional free form of the drug. Also, 
DOX-SL has a half-life of about 48 hours in the bloodstream, 
compared to 10 to 15 minutes for the free drug. No one knows 
for sure why the liposomal drug is targeted selectively to 
the KS lesions. One theory is that these lesions (and also 
cancer tumors) stimulate abnormal blood-vessel growth, 
producing leaky capillaries; the liposomes keep the drug in 
the bloodstream long enough that it has time to leak out into 
the abnormal tissue, while the free drug tends to be 
deposited indiscriminately.

DOX-SL is being developed by Liposome Technology, Inc. (LTI), 
of Menlo Park, California. About 500 people have now used the 
drug as a KS treatment in trials.

Published Experience

The AIDSLINE database, the most complete listing of AIDS-
related journal articles, conference presentations, and 
letters to journals, currently includes 12 citations on the 
use of DOX-SL to treat AIDS-related KS. Most of these reports 
are from Germany. Six of the twelve were presented at the IX 
International Conference on AIDS, June 6-11, 1993, in Berlin. 
Only one of the 12 was published before 1993.

Most of these reports are favorable, suggesting that 
liposomal doxorubicin was effective for the large majority of 
patients, sometimes producing dramatic benefits. But these 
results are not from controlled studies comparing the drug to 
a different treatment regimen. Therefore, we will need data 
from ongoing trials (see below) to evaluate the benefits and 
risks of DOX-SL compared to the available alternatives. The 
FDA usually requires two controlled trials before approving a 
drug.

The main toxicities have been hematologic; these have been 
manageable, sometimes with the help of G-CSF. On the positive 
side, cardiac toxicity (which can occur with ordinary 
doxorubicin) has not been a problem so far; however, this 
effect is cumulative, related to the total lifetime use of 
doxorubicin, so it might appear later after the liposomal 
drug has been used longer.

There are published reports of two deaths from liver failure 
among AIDS patients using DOX-SL; these may have been drug 
related, but that is not known (see Hengge and others -- 
second reference -- and Simpson and others, in References 
section, below). In the only case published in any detail, 
the patient had a history of hepatitis and a T-helper count 
of 17, and had been taking rifampicin, cycloserine, 
clofazimine, fluconazole, and itraconazole, in addition to 
DOX-SL. LTI has not seen any abnormal elevation of liver 
enzymes in its trials, and does not know any other way to 
screen or test for this possible problem.

Most of the reports suggest that liposomal doxorubicin was 
well tolerated, often with no serious side effects, or none 
at all. But clearly there are risks, as with any 
chemotherapy, so the drug will have to be used carefully. The 
phase III protocol includes special testing for cardiac 
toxicity, but no special warning to physicians about the 
possibility of liver problems.

DOX-SL Clinical Trials

Besides the early phase I trial mentioned above, a larger 
phase II (early efficacy) trial of DOX-SL has now been 
completed. The results are not yet available, however, 
because the data is still being analyzed.

Full approval of DOX-SL will also require completion of a 
phase III trial, which began over a year ago and still needs 
about 100 more volunteers; about 125 are already enrolled. 
This trial, now being conducted at over 30 sites in the U.S., 
has been slow to recruit, apparently because lack of 
information or misunderstandings about it.

The trial, which was designed with activist input, is for 
patients with KS which is severe enough to require systemic 
chemotherapy. They are randomly assigned to receive either 
DOX-SL, or the conventional chemotherapy called ABV -- 
Adriamycin (another name for doxorubicin, the active 
ingredient in DOX-SL) plus bleomycin, plus vincristine. 
However, those randomly assigned to ABV will only receive six 
courses of it, at two-week intervals; then they will be able 
to switch to DOX-SL. Also, if the ABV has unacceptable side 
effects, or does not seem to be working, they can switch to 
DOX-SL immediately. (The most serious toxicities of ABV -- 
especially cardiac toxicity which can be caused by the 
Adriamycin -- tend to be cumulative, and unlikely to occur 
early in the use of the treatment.)

Volunteers with any T-helper count can enter this study. They 
must have "progressing KS with at least 25 mucocutaneous 
lesions and/or the development of 10 or more new lesions in 
prior month, and/or documented visceral disease and at least 
2 assessable cutaneous lesions, and/or 2 assessable cutaneous 
lesions with edema." They must have hemoglobin greater than 
8, neutrophil count over 1200, and platelet count over 
75,000. They must not have "active opportunistic infection 
with mycobacteria, cytomegalovirus, toxoplasma, P. carinii or 
other microorganism if under treatment with myelotoxic 
drugs." There are also other inclusion/exclusion criteria.

No placebo is used in this study. Patients are randomly 
assigned to a therapy, but then they are told what they are 
getting.

Why has this trial been slow to recruit? There seem to be 
several reasons. A major one, we believe, is that information 
about the trial has not been effectively communicated. For 
example, we spent well over ten hours researching this 
article before we learned how a patient who wanted to 
volunteer could go about doing so. And as far as we know, the 
list of cities where the trial is being run (see below) has 
never been published before, although a major phase III trial 
has been open for over a year in the U.S. For effective 
recruiting, such how-to-plug-in information should be 
everywhere.

Some volunteers are rejected by the study's entry criteria, 
of course; others are too far from a city where the trial is 
being run. Another problem is that DOX-SL has not been well 
known in the activist community until recently. And many who 
do know about it have wanted to receive it and not risk being 
randomized to ABV -- even though ABV is known to be effective 
in a large majority of cases, and the trial allows everyone 
to get DOX-SL after no more than six courses of ABV. 

Another reason why this trial has been slow to recruit is 
that it does not pay all costs -- and some insurance 
companies have denied reimbursement for the costs which are 
not covered. All the study drugs are paid for -- including 
the ABV, not only the DOX-SL, which of course is provided 
free. And LTI now pays for the cardiograms, which are 
required as a safety measure. But it does not pay the cost of 
the infusions.

Insurance will usually cover this cost (which should not be 
surprising, since the infusions are necessary in any case, 
because patients are not eligible for this trial unless they 
need systemic chemotherapy). In San Francisco, Kaiser San 
Francisco is now preparing to conduct the trial; but it has 
not paid the costs at non-Kaiser sites, so until now it has 
been difficult, even in the San Francisco area, for Kaiser 
patients to enter.

LTI reimburses its trial sites for each patient. Sometimes 
the physician may be willing to give patients a break on the 
infusion cost, if there is no other way to pay for it. If 
financing remains a problem, physicians should call LTI, to 
see if some way that these costs can be paid for.

Expanded Access

In addition to the comparative trials, LTI has made DOX-SL 
available to patients who cannot use ABV successfully and 
have no other option. This expanded-access protocol now has 
about 300 patients enrolled.

Earlier this year LTI closed the expanded access to new 
"refractory" patients -- those for whom ABV does not work -- 
but re-opened it after furious protests from physicians and 
activists. It might be closed in the future, however, as it 
is a serious financial burden on the company, since this 
particular protocol requires major paperwork for each 
patient. Also, this expanded access (which will not 
contribute much toward approval of the drug) appears to have 
reduced recruitment in the all-important phase III trial -- 
as some patients, for example, would get their physician to 
give them ABV just so they could say it didn't work and 
become eligible. The company hopes to replace the current 
expanded access system with a "treatment IND," -- a different 
procedure which would provide the same treatment, but with 
much less documentation overhead. The treatment IND requires 
FDA approval, however, and that is not assured.

Approval Strategy

LTI intends to apply to the FDA for two different marketing 
approvals for DOX-SL. First, it will ask for approval as a 
salvage therapy, for patients who cannot benefit from ABV. 
This kind of application can be considered quickly, based on 
the data that already exists, without waiting for the phase 
III trial to be finished.

LTI will apply for full approval later, after the phase III 
trial is complete.

Pending approval for marketing, LTI hopes to replace its 
current expanded access with a treatment IND, as explained 
above. However, any approval for DOX-SL must go through the 
oncology staff and advisory committee of the FDA -- not the 
same people that usually judge AIDS treatments. The FDA's 
oncologists have little personal experience in treating KS; 
they are experts in cancer, not in AIDS. They may not be 
entirely aware of the need for new treatment options, unless 
oncologists and other physicians let them know what their 
needs are.

Other Trials

In addition to the U.S. trial, a major European trial is 
comparing DOX-SL to a conventional treatment called BV 
(bleomycin plus vincristine) -- a treatment commonly used in 
Europe, apparently to avoid the side effects of the 
Adriamycin. (Although mainly a European study, this trial 
also has three U.S. sites, Boston, Houston, and Seattle; 
however, we do not know at press time if all three are still 
open.)

One future possibility is to combine DOX-SL with BV. This 
would appear to offer the advantage of the three-way 
combination which is the accepted therapy in the U.S., but 
with the presumably better efficacy and lower toxicity of the 
Adriamycin (doxorubicin) component. The AIDS Clinical Trials 
Group (ACTG) of the U.S. National Institute of Allergy and 
Infectious Diseases (NIAID) is now planning a trial, in 
collaboration with LTI, to compare DOX-SL plus BV to DOX-SL 
alone; it could begin as early as summer 1994.

How to Volunteer

DOX-SL trials are currently being conducted in the cities 
listed below (alphabetically, by state); this list only 
includes U.S. sites. Not all trials are available at all 
sites. If more than one physician or medical center is 
conducting DOX-SL trials in a city listed, the total number 
of sites appears after the city name.

Patients interested in more information should have their 
physician call a physician conducting DOX-SL trials in a city 
convenient to them, if their physician knows who that is. 
Otherwise, their physician should call George Tidmarsh, M.D., 
staff oncologist at LTI, 415/323-9011.

California: Berkeley, Encino, Greenbrae, Los Angeles (2), San 
Diego, San Francisco (5)

District of Columbia: Washington
Florida: Miami, Tampa
Georgia: Atlanta (2)
Illinois: Chicago (2)
Massachusetts: Boston, Cambridge
Michigan: Detroit
Missouri: St. Louis
New York: Buffalo (2), New York City (4)
Pennsylvania: Philadelphia
Texas: Dallas, Houston (3)
Washington: Seattle

References

The following are all of the published articles and 
conference presentations we could find on liposomal 
doxorubicin for treating AIDS-related KS. All but one were 
published in 1993. They are in alphabetical order by lead 
author.

Bogner JR, Zietz C, Held M, and others. Ultrasound as a tool 
to evaluate remission of cutaneous Kaposi's sarcoma. AIDS. 
August 1993; volume 7, number 8, pages 1081-1085.

Boyle MJ, Marshall NE, Dolan GM, and others. A phase II study 
of stealth liposomal doxorubicin HCL (S-DXR) in HIV-
associated Kaposi's sarcoma (KS). IX International Conference 
on AIDS, Berlin, June 6-11, 1993 [abstract #1570].

Goebel FD, Bogner JR, Spathling S, and others. Quantitative 
ultrasound volume measurement serves as noninvasive method to 
follow response of cutaneous Kaposi's sarcoma lesions to 
Doxil therapy. PROCEEDINGS: ANNUAL MEETING OF THE AMERICAN 
SOCIETY OF CLINICAL ONCOLOGY. 1993; 12:A7.

Goebel FD, Bogner JR, Spathling S, Held M, Sandor P, and 
Rolinski B. Efficacy and toxicity of liposomal doxorubicin in 
advanced AIDS-related Kaposi sarcoma (KS). An open study. IX 
International Conference on AIDS, Berlin, June 6-11, 1993 
[abstract #WS-B15-6].

Goebel FD, Liebschwager M, Held M, and others. Successful 
treatment of advanced Kaposi sarcoma (KS) with liposomal 
doxorubicin -- short term observations. VIII International 
Conference on AIDS, Amsterdam, July 19-24, 1992 [abstract 
#3108].

Hengge UR, Brockmeyer NH, Baumann M, Reimann G, and Goos M. 
Liposomal doxorubicin in AIDS-related Kaposi's sarcoma 
[letter]. LANCET. August 21, 1993; volume 342, page 497.

Hengge UR, Brockmeyer NH, Rasshofer R, and Goos M. Fatal 
hepatic failure with liposomal doxorubicin [letter; see 
comments]. LANCET. February 6, 1993; volume 341, pages 383-
384.

Jablonowski H, Szelenyi H, Armbrecht C, Mauss S, Niederau C, 
and Strohmeyer G. Liposomal doxorubicin -- a new formulation 
for the treatment of Kaposi's sarcoma: a study on safety and 
efficacy in AIDS patients. IX International Conference on 
AIDS, Berlin, June 6-11, 1993 [abstract #1573].

Northfelt DW, Martin FJ, Kaplan LD, and others. 
Pharmacokinetics (PK), tumor localization (TL), and safety of 
Doxil (liposomal doxorubicin) in AIDS patients with Kaposi's 
sarcoma (AIDS-KS). PROCEEDINGS: ANNUAL MEETING OF THE 
AMERICAN SOCIETY OF CLINICAL ONCOLOGY. 1993; 12:A8.

Sandor P, Bogner JR, Held M, Spathling S, Rolinski B, and 
Goebel FD. Use of G-CSF in the management of chemotherapy-
induced neutropenia in patients with advanced-stage Kaposi-
sarcoma. IX International Conference on AIDS, Berlin, June 6-
11, 1993 [abstract #1890].

Simpson JK, Cottrill CP, Miller RF, and Spittle MF. Liposomal 
doxorubicin: initial experience in a major London centre. IX 
International Conference on AIDS, Berlin, June 6-11, 1993 
[abstract #1603].

Szelenyi H, Jablonowski H, Armbrecht C, Mauss S, Niederau C, 
and Strohmeyer G. Long term treatment with liposomal 
doxorubicin in patients with AIDS-related Kaposi's sarcoma. 
IX International Conference on AIDS, Berlin, June 6-11, 1993 
[abstract #1574].

***** California: AIDS Drug Assistance Program, New Drugs 
      Available April 1

by Bruce Mirken

As we reported in the last two issues of AIDS TREATMENT NEWS, 
California recently added 13 new medications to its AIDS Drug 
Assistance Program (ADAP), as a result of new Federal funding 
through the Ryan White CARE Act. A total of 27 drugs (see 
below) are now approved for this program for uninsured 
persons with low or moderate income. But we recently learned 
that the 13 new drugs will not be available at least until 
April 1, when the Federal funding is received.

There could be an additional wait in some counties, due to 
paperwork. This happened the last time there was major 
expansion of the program, when some county health-department 
officials did not move quickly to make the newly added drugs 
available.

Steven Roger, Chief of Early Intervention Services for the 
California state Office of AIDS, said he is confident that 
the new drugs will be available after April 1 without delay. 
We asked what clients should do after that date if they 
encounter local officials either unaware of or unable to 
provide the newly added medicines. "Call me," he replied. His 
number is 916/327-6784.

Activists are concerned that the program has been 
inadequately publicized, and Roger says he is considering an 
informational mailing to all California physicians -- if he 
can find the time and resources. "There's just so much we can 
do," he commented. "We've got a really small staff."

Readers outside of California should note that similar 
programs are available in most states, but the lists of 
available drugs and other details vary considerably. Your 
local health department or AIDS service organization may be 
able to provide information for your area.

The following drugs are now included in the California AIDS 
Drug Assistance Program: acyclovir*, amphotericin B*, 
atovaquone*, azithromycin*, AZT, clarithromycin*, 
clindamycin, clofazimine*, clotrimazole, dapsone, ddC*, ddI, 
ethambutol*, flucytosine*, fluconazole, foscarnet*, 
ganciclovir, ketoconazole, nystatin, paromomycin*, 
pentamidine (aerosol), pentamidine (intravenous)*, 
pyrimethamine, rifabutin*, sulfadiazine, trimethoprim-
sulfamethoxazole. Those marked with the asterisk should be 
available after April 1.

Note: In California and probably most other states it is 
usually necessary to go to the county pharmacy or other 
special locations to receive ADAP drugs. Some states provide 
the drugs by mail or through ordinary pharmacies, apparently 
reducing administrative costs as well as hardship for some 
patients.

***** FDA Holds Buyers' Club Drugs: Review of Access Issues

by John S. James

Since February 22, three packages of pharmaceuticals shipped 
from Mexico to the PWA Health Group in New York have been 
held by the Cincinnati office of the U.S. Food and Drug 
Administration. On March 16, as this issue goes to press, one 
of the three has been released; the other two are still being 
held. The PWA Health Group has openly imported all three of 
the drugs involved for several years; however, the FDA 
insists that there has been no change in policy. (The drugs 
are: albendazole -- now released -- used for treating 
microsporidiosis, when nothing else works; tinidazole, an 
anti-parasite drug which works more quickly than Flagyl; and 
isoprinosine, an immune modulator which has shown good 
results in a major Scandinavian trial with hundreds of 
patients, but was never developed in the U.S. because 
political disputes held it up until the patent ran out. The 
PWA Health Group has long required a prescription for 
albendazole and for tinidazole, but not for isoprinosine, 
which is commonly sold over the counter.)

The current incident did not result from any problem with the 
drugs, nor from any policy change. What precipitated it is 
that the PWA Health Group switched to a different shipping 
company, whose flights from Mexico to New York connect 
through Cincinnati. Two agents in the FDA office there held 
up the drugs. After the PWA Health Group called the Office of 
AIDS and Special Health Issues, at the FDA headquarters near 
Washington, to get the shipments released, the Cincinnati 
agents called physicians who had written albendazole 
prescriptions, "to warn the doctors about participating in a 
'drug smuggling ring' with 'potential for criminal charges' 
if they don't comply with the investigation," according to a 
March 7 memo from the PWA Health Group. Sally Cooper, 
executive director of the PWA Health Group, told us that the 
physicians she talked to were outraged by this attempt to 
interfere with their medical practice, when their use of the 
drug is widely accepted as reasonable by experts in the 
field. But they were unwilling to write or call the FDA about 
it, apparently fearing that they might make enemies who could 
hurt them in their profession. The PWA Health Group 
complained to the FDA; but after an internal FDA meeting on 
March 4, they were told that the AIDS office was no longer 
handling this issue and they had to work through the Office 
of Regulatory Affairs.

While the immediate problem may be resolved -- largely by 
using other freight carriers, so that packages will no longer 
be shipped through Cincinnati -- there are larger issues 
around the edges. While it appears true that there has been 
no change in official FDA policy, there are concerns that 
this case, among others, may signal changes in attitude. 
Problems cleared up years ago not only have returned, but 
have been more difficult than expected to resolve.

Background: FDA Personal-Use Import Policy

The regulations involved in this case concern the much-
discussed FDA policy on importing small quantities of 
pharmaceuticals, not available in the U.S., for personal use. 
This policy was formalized in December 1989; it was modified 
on May 25, 1993, in a letter from the FDA to AIDS buyers' 
clubs, and is in force today. Because of considerable 
confusion about the policy, we reproduce the key section, 
dated December 11, 1989, from the Regulatory Procedures 
Manual. (We also include the section which follows, on import 
alerts, although it is not involved in the Cincinnati case.)

9-71-30 GENERAL GUIDANCE

 Section C. Drugs, Biologics, and Devices

When personal shipments of drugs and devices that appear 
violative are brought to FDA's attention by Customs, FDA 
personnel will have to use their discretion to decide on a 
case by case basis whether to sample or detain. Generally, 
drugs and devices subject to the Import Alerts are not 
amenable to this guidance. Devices to be used by 
practitioners for treating patients should not be viewed as 
personal importations subject to this chapter. Drugs subject 
to Drug Enforcement (DEA) jurisdiction should be returned to 
Customs for handling.

In deciding whether to exercise discretion to allow personal 
shipments of drug or devices, FDA personnel should consider a 
more permissive policy in the following situations:

* when the intended use is appropriately identified, such use 
is not for treatment of a serious condition, and the product 
is not known to represent a significant health risk; or

* when 1) the intended use is unapproved and for a serious 
condition for which effective treatment may not be available 
domestically either through commercial or clinical means; 2) 
there is no known commercialization or promotion to persons 
residing in the U.S. by those involved in the distribution of 
the product at issue; and 3) the product is considered not to 
represent an unreasonable risk; and 4) the individual seeking 
to import the product affirms in writing that it is for the 
patient's own use (generally not more than 3 month supply) 
and provides the name and address of the doctor licensed in 
the U.S. responsible for his or her treatment with the 
product or provides evidence that the product is for the 
continuation of a treatment begun in a foreign country.

Where there are any questions about the application of these 
factors to any product, the product should be detained and 
FDA personnel should consult with the appropriate 
headquarters office.

Where a shipment is not detained or refused, FDA personnel 
should "Release with Comment" and, as appropriate, advise the 
recipient that 1) the drug (or device) that has been obtained 
for personal use appears to be unapproved in the United 
States; 2) the drug (or device) should be used under medical 
supervision; 3) FDA may detain future shipments of this 
product; and 4) the patient's physician should consider 
enrolling the patient in an Investigational study or applying 
for an Investigational New Drug (IND) exemption.

9-71-40 IMPORT ALERTS

FDA personnel should recommend to HFC-131 the issuance of an 
import alert if they encounter:

* personal importation of products that represent either a 
direct or indirect risk;

* the promotion of unapproved foreign products for mail-order 
shipment; or

* repeated importation of products that represent a health 
fraud.

This policy was updated in the May 1993 letter to buyers' 
clubs (see AIDS TREATMENT NEWS #176, June 4, 1993, for 
portions of that letter, and for an interview with Randy 
Wykoff, M.D., head of the FDA's Office of AIDS and Special 
Health Issues). The letter interpreted the 1989 policy to 
address three major concerns of the FDA: lack of physician 
involvement in the care of people getting products through 
alternative mechanisms; promotion and commercialization of 
products; and drugs from unknown sources.

Neither the original policy nor the clarification requires a 
prescription for drugs to be imported. Instead, from the 
letter to buyer's clubs:

"Documentary evidence should be available for immediate 
review onsite, demonstrating that any patient importing 
products for personal use has a licensed physician who is 
accepting responsibility for the patient's care, including 
the administration of the imported product. FDA does not 
believe that the best interests of any individual are served 
by having access to drugs for serious conditions without 
adequate physician oversight."

Comment and Recommendations

The PWA Health Group appears to have more than met the 
requirements of the personal use policy. The policy does not 
require a prescription, only evidence that a physician is 
supervising the treatment -- a matter which activists fought 
hard for in 1989, when the policy was developed. The PWA 
Health Group does require a prescription for albendazole and 
tinidazole.

Persons should be aware, however, that the personal-use 
import policy allows discretion by the FDA, and provides 
guidance to agents on using that discretion. It does not 
create a legal right to import drugs in every case, but 
attempts to formalize procedures for making case-by-case 
decisions.

The issue, then, is one of discretion. During the last 
several years the FDA has made important efforts to avoid 
being an obstacle to persons with AIDS or other serious or 
life-threatening conditions obtaining treatment which is 
medically appropriate. And usually the problem now is no 
longer the FDA, but the lack of interest by pharmaceutical 
companies in developing products for AIDS, and especially for 
opportunistic infections, since the U.S. market for each 
infection is likely to be small.

The Cincinnati incident has precipitated fears that the FDA 
may be diluting its commitment to avoid blocking patients' 
access to unapproved but medically appropriate care for 
serious conditions for which no adequate approved therapy is 
available.

The FDA appears to be concerned that if it uses its 
discretion in favor of persons with life-threatening 
conditions -- and AIDS in particular -- then promoters of 
health foods or questionable remedies can argue in court that 
they are victims of discriminatory enforcement, that the FDA 
is giving special breaks to people with AIDS that it is not 
giving to them. In fact, under the laws and regulations, the 
FDA is clearly given areas of discretion, and is expected to 
exercise this discretion in the furtherance of medically 
rational policies. But attitudes toward AIDS in some parts of 
the country are such that the promoters' discriminatory-
enforcement argument could have influence, regardless of 
laws, regulations, or rationality. We understand that the FDA 
recently lost a case in which that argument was raised -- 
apparently a bizarre case which started by accident but 
turned into a decade-long crusade. The FDA may also be 
concerned that overruling local officials' moves against AIDS 
groups may damage morale -- even though the regulations 
plainly state that local officials should seek guidance from 
FDA headquarters when questions arise.

Meanwhile, the recent events are raising fears about whether 
the AIDS community can still defend itself. Many people have 
died, and there is widespread discouragement due failures in 
treatment research; will people still mobilize if necessary 
to maintain access to medically appropriate treatments, when 
their access is under political attack? This is why the small 
incident in Cincinnati invokes issues which will not go away.

We have two suggestions -- not for the immediate case, but 
for building strength to be used if necessary in the future. 
First, we can begin groundwork on what could be a powerful 
response to official obstacles to medically accepted 
treatments -- actions for wrongful death, raising the issue 
in the courts, Congress, the media, and otherwise, in cases 
where the lack of treatment appears to cause or contribute to 
the death. The way to prepare for this possibility is for 
organizations to do the advance work to handle the obstacles 
-- legal, financial, technical -- to such actions. If the 
preparations are thorough and professional, then all that 
will be necessary, when an appropriate case arises, is for 
the family or other representative -- or for the deceased 
themselves, through a will -- to say, "Yes." It would not 
take many such cases to have an impact.

Our other suggestion for building community strength is much 
broader. AIDS and treatment organizations need to make 
certain changes in how they operate, in order to be able to 
grow into a mass movement. (AIDS may not be a mass movement 
in itself, but needs to be able to function as part of one, 
in coalition with others.) The main problem is that most 
organizations do not offer a workable path for new people to 
approach the group and get plugged in -- an easy, appealing 
way to volunteer, or just to hang out for a while with as 
little or as much commitment as they want to give, and see 
what develops for them. AIDS organizations which do offer a 
clear, unambiguous path (such as the Walkathon, etc.) often 
get tens of thousands of volunteers; people are ready to 
help, but organizers must do their job first to make it 
possible for them to do so. The elitism and ego fights, which 
can occur in any organization, can poison the development of 
the mass-movement style which may become necessary for our 
survival.

***** AIDS TREATMENT NEWS
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AIDS TREATMENT NEWS reports on experimental and 
standard treatments, especially those available now. We 
interview physicians, scientists, other health 
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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 1994 by John S. James.  Permission granted for 
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