Subject: FDA and Egg Lipid Company Date: Mar 11 1988 (552 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& copyright 1988 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS Issue # 52, March 11, 1988; also published (in part) in SAN FRANCISCO SENTINEL, same date. by John S. James CONTENTS: [***** appears here at each new item] FDA Moves Against Egg Lipid Company Ribavirin and Mortality: New Information Trimetrexate With Leucovorin: Decisions That Save Lives, Decisions That Kill Announcements: Naltrexone Safety Note: Dosage Error Pharmacy Price List Available ***** FDA Moves Against Egg Lipid Company (March 15) On March 2 the U. S. Food and Drug Administra- tion (FDA) ordered Houba, Inc. of Culver, Indiana to stop manufacturing and selling its lipid product EL 1020 (which some have compared to AL 721). The letter said that "...promotional activities which accompanied the initial shipment of EL 1020 sug- gested that the article was intended for use in the treatment of acquired immunodeficiency syndrome (AIDS). Because such promo- tional activities included statements which represented and sug- gested that this article was intended to be used in the cure, mitigation, treatment, or prevention of disease, or was intended to affect the structure or any function of the body of man, this product is a drug within the meaning of Section 201(g) of the Federal Food, Drug, and Cosmetic Act." The letter also said that the product was "misbranded in that its labeling does not contain adequate directions for use as this term is defined in 21 CFR 201.5 since the conditions for which it is offered are not amen- able to self diagnosis and treatment by the laity; therefore ade- quate directions cannot be written under which the layman can use this drug safely and for the purposes for which it is intended." The letter gave Houba ten days to answer detailed questions con- cerning how it was going to discontinue its manufacturing and marketing of EL 1020. No one has alleged that there is anything harmful about the product; the dispute concerns how it was marketed. This FDA action caused great concern in the AIDS community, as nobody knows exactly why Houba was singled out, and whether the FDA will try to cut off all supplies of egg lipids, which are used by thousands of people. In the week since the FDA action became known, AIDS advocates have conveyed community concerns to high officials in the FDA. Fears have eased somewhat, although the final outcome is still unknown. Background On Houba Houba differs from all other suppliers of egg lipid products in several ways: * Its subsidiary, Rachelle Laboratories, Inc., which manufactures and sells the EL 1020, is a pharmaceutical company which deals routinely with the FDA. * Until last year, Houba had manufactured the official AL 721 for Ethigen Corporation (formerly Praxis Pharmaceuticals), which holds worldwide licensing rights acquired from the Weizmann Institute of Science in Israel, which developed the product, and also holds the copyright on the term "AL 721". Houba's new pro- duct provides the egg lipids in a syrup form which differs from AL 721. * Houba planned to sell its product primarily or exclusively through HIV-positive buyers clubs, such as the PWA Health Group in New York, or the Healing Alternatives Buyers Club (HABC) in San Francisco. (The New York group has sold one of two forms of EL 1020; the San Francisco-based HABC has not carried either.) * At about the same time as the three-month FDA investiga- tion of Houba, the company was subjected to sensationalized news- paper articles in a South Bend, Indiana paper. The first article said that Houba was doing secret AIDS research, and that a resident of Culver, Indiana, where the factory is located, was concerned that there may be a health hazard from materials used. A source within Houba told us that this article raised such panic that the AIDS virus may be on the premises that there was fear that the factory could be burned down. To avert possible violence Houba gave the newspaper informa- tion on what they were in fact doing, which had nothing to do with the AIDS virus. The publication of this information reduced the panic, but it may also have constituted some or all of the "statements which represented and suggested" that the product was to be used for AIDS. The newspaper followed up with a headline and story that Houba's "AIDS drug" lacked FDA approval. Accord- ing to a source within Houba, the newspaper later learned about the FDA order against Houba before the company itself did. AIDS Community Concerns Official approval of AL 721 is one to several years away. Almost no progress has been made toward approval in the last two years. Meanwhile, several thousand people with AIDS or ARC have started using egg lipid food products; the current generation first became available in April of last year. Many are convinced that these have been a major help to them, while others have found no effect. So far the FDA has avoided direct attacks against the AIDS treatment community, so the first concern about the Houba action was whether this policy was changing. A war between the FDA and persons with AIDS could seriously harm both. The AIDS community fears increased difficulty in access to treatments, and diversion of energy which should go to better use in the AIDS crisis. The FDA fears bad publicity, as it knows that Congress can enact laws to take some of its powers away, as it has done at least once in the past (when the FDA tried to make vitamin pills exceeding government-recommended dosages into prescription drugs). Both sides have strong incentives to compromise. The AIDS community is also concerned about what precedent this case sets. The FDA has the power to declare that a product is a drug (when it would otherwise be a food) even in the absence of any medical claims by the manufacturer -- if the manufacturer's marketing targets a specific group such as persons likely to use the product as a drug. This means that the mere fact that a manufacturer sells a product to AIDS treatment organ- izations could be used against it -- setting up a new kind of AIDS discrimination, government inspired or even government required, whereby private manufacturers are forced to boycott AIDS groups and cut off supplies of potential treatments. The same situation could apply to persons with other diseases. But with AIDS at least, this problem is far from academic; it has already had serious consequences. The availa- bility of egg lipid products was delayed last year, probably for several weeks, when the first manufacturer found to have a suit- able product refused to sell to anyone involved with persons with AIDS. And today, the only company in the world which makes the old Salk polio vaccine is refusing to sell it to physicians who want to try it as an AIDS treatment, despite serious scientific interest in this possibility and good early results. The FDA, which may NOT be responsible for the problem in this case, has no legal right to stop physicians from using an approved drug for a non-approved use, which physicians can legally do; but a private company can refuse to sell its product to anyone, even physicians engaged in the completely legitimate practice of medicine, even when it is the world's sole supplier. The history of the AIDS epidemic is loaded with obstacles to treatment access and prompt treatment research. The AIDS treatment community wants to handle these problems in ways that avoid unnecessary fighting on the one hand, and compromises embodying destructive precedents on the other. We interviewed two AIDS treatment advocates who are FDA experts and have been in close touch with FDA officials in the week since they learned about the Houba case. Both have dif- ferent views of a murky situation. It is clear that the outcome has not yet been determined. To Martin Delaney, co-founder of Project Inform in San Fran- cisco, the key issue is whether the FDA pursues the case against Houba only on the basis of statements made by Houba -- facts which apply to that immediate case and do not spill over to involve the larger AIDS treatment community. But if the FDA chooses to prosecute Houba because it sold its product largely or exclusively to HIV-positive buyers clubs, the precedent would contribute to discrimination by telling suppliers that their pro- ducts could be classified as drugs and banned if they sold them to AIDS groups, even though the identical products would remain foods if sold in health-food stores or otherwise to the public in general. At this time Delaney has heard that the FDA has weighed the various considerations and chosen not to use the sales to buyers clubs against Houba in this case. Another FDA expert, Jay Lipner, a volunteer attorney who works with Lambda Legal Defense in New York and has worked closely with Martin Delaney on this issue, sees the outcome as still to be determined. He sees only that some progress has been made in clarifying for the FDA what the viewpoint is of some members of the gay community. "The facts and the law remain complex and confusing," said Lipner. "The one clear message so far is that the AIDS community must have long-term, ongoing, professionally assisted advocacy on treatment and research issues. Otherwise even the most basic interests of persons with AIDS will not be protected." ***** Ribavirin and Mortality: New Information This reporter obtained previously-unpublished information comparing persons with ARC who chose to use or not use ribavirin after finishing major clinical trials conducted at four medical centers in 1987. The numbers look very good, but they are not conclusive because of the way self-selection worked in this case. After the patients completed a double-blind placebo study of ribavirin, they were entitled to obtain the drug free if they wanted it, in return for their participation in the study. A total of 116 patients (from both the ribavirin and placebo groups) did choose to use the drug in this "open-label" phase of the study; 74 chose not to. In the 116 who did use ribavirin there were 6 deaths (5 percent), but in the 74 who did not use ribavirin there were 25 deaths, or 34 percent. Some of these patients had been on ribavirin for as long as 80 weeks; others, in the placebo group in the original study, had been using the drug for less time. These figures look conclusive, but they could have happened by self selection. Suppose ribavirin didn't do anything. The patients who happened to be doing well while on ribavirin in the study would be likely to want to stay on the drug, since it would have seemed to be working for them. But those patients who hap- pened to be doing poorly would be likely to drop the drug in order to switch to AZT, which cannot be combined with ribavirin. The result is that those who were doing well would tend to put themselves into the ribavirin group, while those doing poorly would go into the other group. This self selection of healthier patients into the ribavirin group during the open-label phase of the study could have caused a difference in death rates, even without any effect from the drug. It may be possible to analyze the patient records to see how much of the difference in death rate could be attributed to self selection and how much to the drug. This analysis will almost certainly require subjective judgments. And ribavirin has become so politicized that it will be hard to trust this judgment to any researchers not truly independent of both the drug's manufacturer and the FDA. We don't know how such a study could be arranged. In the absence of better information, it seems unlikely to us that this large difference in death rate could be explained solely by self selection -- especially since all patients enter- ing the trial had to meet medical inclusion criteria designed to give a fairly homogeneous group for the study. Instead, this information seems to fit with anecdotal reports that some persons have stopped using ribavirin and quickly deteriorated, whereas others stopped it and had no change. It is possible that ribavi- rin delays certain stages of progression of HIV infection, while having little or no effect at other stages. It may be possible to study this question by using newer diagnostic tools, such as the P-24 antigen test. Ribavirin Update On January 15 we published a short article, "Ribavirin Available By Prescription?". We have since heard from Roberts S. Smith, a director of ICN Pharmaceuticals (the manufacturer of ribavirin), and of Viratek (the ICN subsidiary which developed the drug). He asked us to make it clear that ICN had nothing to do with the plans described in the article, and that to the best of his knowledge their product was not being used. Ribavirin By Prescription? Ribavirin has been available in the U. S. by prescription for some time, but the only FDA-approved use has been for aerosol treatment of respiratory syncytial virus in infants. Physicians are, however, allowed to use an approved drug for other than approved uses. (An excellent discussion of this issue appeared in the FDA Drug Bulletin Volume 12 Number 1, April 1982. It points out that gaining FDA approval for legitimate medical advances "may take time and, without the initiative of the drug manufacturer whose product is involved, may never occur. For that reason, accepted medical practice often includes drug use that is not reflected in approved drug labeling." (You can get the FDA Drug Bulletin from a Federal depository library -- which can be found in most cities.) Recently we heard from a pharmacist that he could fill prescriptions for ribavirin if the physician specified that it be used "as directed". This would be the official ribavirin, not an imitation product. However we have not heard from anyone who has actually obtained and used the drug in this way. And according to Martin Delaney of Project Inform, ribavirin is sold only through hospi- tals, since the aerosol treatment for infants is not suitable for home use. If a pharmacy does have the drug, we suspect that the words "as directed" get the pharmacist off the hook, leaving the issue of prescribing ribavirin for treatment of AIDS or ARC between the physician and the FDA. And physicians as a group have long been protective of their right to practice medicine as they see fit; they have considerable political power when they use it, and when the laws were written they were careful to guard their profes- sional sphere against intrusions. Pharmacists in this country do not have the same protections. The phrase "as directed" apparently works its magic by not giving notice to the pharmacist of the non-approved use. Ribavirin is of course a special case, in that a state of war has developed between ICN, the manufacturer, and the FDA. ICN has not always played by the rules -- rules of a game which has grown to be rigged against small to medium companies like ICN, in favor of giants like Burroughs-Wellcome. We don't know who will win this war, but tragically we do know who will lose it. No one knows for sure whether ribavirin does any good for persons with ARC or AIDS, but few could have confidence in the system currently in place for finding out. We should add that ICN had nothing to do with our comments here, and knew nothing about them in advance. While physicians are allowed to prescribe approved drugs for non-approved uses, drug manufacturers are strictly forbidden to do anything to encourage them to do so. And physicians have been reluctant to exercise or even dis- cuss the rights they have -- possibly from fear of losing profes- sional flexibility if the issue came to a head. Physicians have already lost influence and freedom in the face of Federal efforts to control medical costs. The big money in medicine, which so enriched U. S. allopathic physicians by legislating rival systems out of existence earlier in the twentieth century, may turn against its beneficiaries now that bigger money is involved. ***** Trimetrexate With Leucovorin: Decisions That Save Lives, Decisions That Kill On February 16 the U. S. Food and Drug Administration (FDA) and the National Institute of Allergy and Infectious Diseases (NIAID) approved the first-ever "treatment IND" for early release of an AIDS treatment -- trimetrexate with leucovorin for pneumo- cystis. The AIDS community rightly welcomed this step forward -- the first AIDS use of the FDA's widely publicized "new rules" intended to allow physicians to use promising drugs before full approval for commercial sale, in cases of serious or life- threatening illnesses. If it works as intended, the new approval should save many lives. Unfortunately the trimetrexate ruling also contains a tragic flaw which will almost certainly result in many deaths of others who could be saved. Background On October 15, 1987 The New England Journal of Medicine pub- lished a major article on a new treatment for pneumocystis (Allegra and others, 1987). Trimetrexate, an experimental anti- cancer drug, had been found to be 1500 times more powerful than trimethoprim, part of a standard treatment, for inhibiting an enzyme obtained from the protozoa which cause pneumocystis. The dose of trimetrexate required to treat pneumocystis is potentially lethal; but an antidote, leucovorin, can be used to rescue human cells. Protozoa, such as pneumocystis, cannot use leucovorin. A trial of the trimetrexate/leucovorin combination with 49 patients found clearly better survival than would have been expected for those patients with standard treatments. And the new drug combination had very few side effects; only one of the 49 patients had drug intolerance serious enough to require discontinuing the treatment. Most significantly, the trimetrex- ate treatment saved 11 of the 16 patients who could not use either of the standard therapies (intravenous bactrim or pentami- dine), either because they had severe side effects or because they had been ineffective. The New Approval: Who Can, Who Cannot Qualify Under the new approval announced February 16, the NIAID will provide trimetrexate only for patients who have shown "a severe or life-threatening adverse reaction to the approved therapies" (quote from FDA/NIAID press release). The drug, available only from the NIAID, will NOT be provided for patients for whom stan- dard therapies have merely proven ineffective -- but not caused severe or life-threatening toxicities. These patients will be left to die. This ruling flies in the face of the recommendation of the eleven physicians who wrote the October 15 article in the New England Journal of Medicine. Their abstract concludes "that the combination of trimetrexate and leucovorin is safe and effective for the initial treatment of pneumocystis pneumonia in patients with AIDS and for the treatment of patients with intolerance or lack of response to standard therapies". A spokesman for Warner Lambert, the manufacturer of trimetrexate, said that the restriction (against using the drug when all standard treatments had failed to work, though they had not caused a severe or life-threatening reaction) was an FDA decision; it had been explained to him once but he didn't recall the rationale. A spokesman for the FDA gave two reasons. First, the drug had not been approved; clinical tests had not been com- pleted. Second, it is not a drug to be used lightly, as it was potentially lethal unless leucovorin was also administered. When we asked how these reasons applied when the only alternative was the death of the patient -- and the trimetrexate/leucovorin com- bination almost never had side effects severe enough to cause its use to be discontinued -- he had no meaningful answer but sug- gested we talk to the NIAID, which developed the protocol (with the help of the FDA, which approved it). He did say that indivi- dual cases might be considered under an emergency treatment IND -- an option we believe unlikely to happen in actual hospital practice, especially since physicians would be applying for some- thing explicitly not allowed in the new NIAID/FDA protocol. He also said that the question of whether to expand the conditions under which physicians could use the drug was now being con- sidered by NIAID. NIAID said, however, that the exclusion of patients for whom all standard treatments failed was an FDA decision. NIAID is now working on "protocol 30", which is designed for these patients; we have not seen protocol 30 since it has not yet been released, but it is part of a series of protocols designed for scientific use, not treatment access, so presumably it will have selection criteria which exclude many patients for whom trimetrexate treat- ment would be medically indicated. We do not know why these patients were excluded from the treatment IND (which is designed for treatment access), since no one involved will take responsibility for this decision. The best guess is that the reason for it was to force a selected group of the patients affected into protocol 30. Most of the others will end up in the morgue. The public had no input this decision, hidden in the fine print of the first AIDS-related treatment IND, which was announced by surprise at the time of two major meetings where it was important for the FDA to look good. Persons with AIDS, and as far as we know their physicians, also had no input. Unless compelling new information has developed since last October -- information unknown to the press offices of either the drug manufacturer or the FDA -- this access restriction could only be called a ghoulish decision to deny trimetrexate to pneumocystis patients for whom all other available treatments have failed -- despite the clear recommendation of the world's leading experts on the trimetrexate treatment, based on their published evidence. The press, which usually only rewrites official news releases on medical-treatment stories, largely missed what happened here. The February 16 NIAID/FDA press release saw the matter as follows: "'Today's action reaffirms FDA's commitment to broaden early patient access to promising experimental treatments for AIDS, AIDS-associated conditions and other life-threatening diseases,' said FDA Commissioner Dr. Frank E. Young, PhD. availability to those people with AIDS who could potentially benefit from it brings us another step forward in treating one of the most devas- tating infections seen in AIDS. ' "NIAID Director Dr. Anthony S. Fauci said, "This treatment IND will allow us to offer an important treatment alternative to severely ill patients who cannot tolerate the standard therapy. It is also an example of how NIH is meeting one of its major goals -- enabling community physicians to select the most appropriate therapies for their patients with AIDS. '" (Note: We should add that aerosol pentamidine treatment -- also highly safe and effective, though not yet approved -- should be another treatment option. But even at San Francisco General Hospital, which developed the treatment and knows it better than anyone else, red tape and institutional fears of using a non- approved treatment have kept it out of reach of many patients. The October article on trimetrexate did not discuss aerosol pen- tamidine.) Physicians who want details on this distribution of trimetrexate /leucovorin can call an NIAID hotline, (800) 426- 7527, except from Michigan where the number is (800) 833-0014, between 8AM and 8PM EST, Monday through Friday. We asked at FDA whether physicians should start paperwork in advance, as the drug might be needed in an emergency. We were advised that the most important thing was to keep patient records up to date, as physi- cians must prove that there had been severe or life-threatening reactions to the standard treatments before obtaining the trimetrexate. References Carmen J. Allegra, M. D., Bruce A. Chabner, M. D., Carmelita U. Tuazon, M. D., Debra Ogata-Arakaki, R. N., Barbara Baird, R. N., James C. Drake, B. S., J. Thayer Simmons, M. D., Ernest E. Lack, M. D., James H. Shelhamer, M. D., Frank Balis, M. D., Robert Walker, M. D., Joseph A Kovacs, M. D., H. Clifford Lane, M. D., and Henry Masur, M. D. Trimetrexate For the Treatment Of Pneumo- cystis Carinii Pneumonia In Patients With the Acquired Immunode- ficiency Syndrome. The New England Journal of Medicine, volume 317, pages 978-985, October 15, 1987. ***** ANNOUNCEMENTS Naltrexone Safety Note: Dosage Error A typographical error in the October 1987 AmFAR Directory of Experimental Treatments for AIDS and ARC caused the recommended dose of naltrexone to be listed erroneously as "1.75 mg/kg". The intended dose was 1.75 mg per day. The erroneous dose was over 50 times too large and is potentially harmful. A photocopy of the section containing the error also went out (together with correct information) with material from Pro- ject Inform. Meanwhile Bernard Bihari M. D., the developer of the nal- trexone AIDS/ARC treatment, has increased the recommended dose from 1.75 mg per day to 2.75 mg per day. For complete instructions including all the corrections, contact Project Inform, (800) 822-7422 from outside of Califor- nia, (800) 334-7422 from within California, or (415) 928-0293 from anywhere. ***** Pharmacy Price List Available David J. Flores of San Francisco checked prices of drugs commonly used by persons with AIDS or ARC, at five different pharmacies in San Francisco. Prices usually varied by about 20 percent, in a few cases much more. The drugs included AZT, Acy- clovir, Mycelex, Mycolog II, Halcion, Septra DS, Ketaconazole, Ativan, Trimethoprim, Dapsone, and Atarax; prices were for equivalent generics when available. Persons near San Francisco can use the list directly; persons elsewhere can check the price ranges to see if they are paying too much. We commend Mr. Flores for the public service of putting this list together. To obtain a copy, send a self-addressed stamped envelope to: David J. Flores, 724 Kansas St., San Francisco, CA 94107. [Note: the list is on display here, Open Forum #189. -- sysop] ***** [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display