From: "John S. James" Date: 19 Mar 94 14:58 PST Subject: AIDS TREATMENT NEWS #195 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 Published twice monthly Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141 800/TREAT-1-2 toll-free U.S. and Canada 415/255-0588 regular office number fax: 415/255-4659 Internet: aidsnews.igc.apc.org Editor and Publisher: John S. James Reader Services and Business: David Keith Thom Fontaine Tadd Tobias Rae Trewartha 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. Subscription Information: Call 800/TREAT-1-2 Businesses, Institutions, Professionals: $230/year. Nonprofit organizations: $115/year. Individuals: $100/year, or $60 for six months. Special discount for persons with financial difficulties: $45/year, or $24 for six months. If you cannot afford a subscription, please write or call. Outside North, Central, or South America, add air mail postage: $20/year, $10 for six months. Back issues available. Fax subscriptions, bulk rates, and multiple subscriptions are available; contact our office for details. Please send U.S. funds: personal check or bank draft, international postal money order, or travelers checks. VISA, Mastercard, and purchase orders also accepted. ISSN # 1052-4207 Copyright 1994 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.