The outline of a compromise to an intense dispute about access to thalidomide as a potential treatment for wasting syndrome -- a dispute that could have led to FDA raids on the largest AIDS buyers' clubs -- appears to have been reached at an October 24 meeting of the buyers' clubs, thalidomide developer Celgene Corporation, and the FDA. Under this compromise, physicians will be able to choose a dose of 50, 100, or 200 mg per day (the most common dose has been 100 mg), under an open-label safety study; patients will have to pay for the drug, with the price not yet worked out. (An earlier plan, which would have had patients pay for the drug without controlling which dose they got, raised concerns that it would set a dangerous precedent of allowing companies to charge volunteers for entering a randomized clinical trial.)
The buyers' clubs -- the PWA Health Group in New York, and Healing Alternatives in San Francisco -- have worked for over two years so that people with AIDS-related wasting could get thalidomide under some form of official compassionate-access system. When the drug remained unavailable outside of a restrictive clinical trial, they organized a special Thalidomide Underground Compassionate Use Program, in order to force the creation of an official program. This goal now seems to have been reached. When the new open-label safety protocol is functioning, the underground program will end.
Background: Wasting Syndrome
Wasting syndrome -- extreme loss of lean body mass -- kills many people with AIDS. It has many different causes, and there is no single treatment for everyone. The first step in prevention or treatment is diagnosis and correction of a specific cause, such an intestinal infection, or an obstacle to sufficient food intake. Nutritional and life-style counseling can also be important, especially for early intervention and prevention. But there are many cases that do not respond to these approaches.
The FDA has approved treatments for wasting syndrome: megestrol acetate (Megace(TM)), and dronabinol (Marinol(TM), which uses the active ingredient of marijuana to stimulate appetite). For some people these are helpful; for others they are not. Both are expensive. Smoked marijuana appears to work better than the dronabinol pills for some people (for others, the pills are better), but marijuana is illegal. TPN (total parenteral nutrition, a very expensive intravenous feeding) can help in certain specific cases. Other possibilities are mentioned below.
When other treatments have failed, some of the best results seem to have come from human growth hormone -- a very expensive prescription drug which has been FDA-approved in the U.S. for years for treating short stature in children, but has been tightly controlled to prevent abuse by athletes. Human growth hormone is now available to treat wasting syndrome in certain cases under a "treatment IND" -- a special FDA program which is intended to allow compassionate use of a drug when urgently needed by a group of patients, and which can allow companies to charge for "cost recovery" in supplying these drugs. The problem is that human growth hormone costs about $1,000 per week under the treatment IND, and will probably need to be used indefinitely. Some people can get coverage under insurance, Medi-Cal in California, or an indigent-patient program.
The prescription versions of this drug are even more expensive. Incidentally, a similar hormone for cattle costs over a thousand times less. It cannot be used by people; we mention it to show that investigation is needed into how the price of human growth hormone has stayed so uniformly high for so long all over the world, despite the fact this drug is manufactured by a number of different and supposedly competing companies, and manufacturing cost is apparently not an issue. There are patents, but they have not effectively provided a monopoly; something other than the patents must be keeping the price very high.
Because no single treatment for wasting syndrome works for everyone, and because several of the major treatments are economically out of reach for most people, there is urgent interest in low-cost options. The main ones now being examined are (1) anabolic steroids and/or testosterone, and (2) thalidomide. [In addition, thalidomide might also have other uses in AIDS; see "Thalidomide and Kaposi's Sarcoma -- Call for Information," below.]
Background: The Thalidomide Controversy
For some time thalidomide has been available through an FDA- approved program for compassionate use in treating certain AIDS-related aphthous ulcers which have not responded to other therapies. Until recently this program was not open to persons with wasting syndrome. Such persons had no way to get thalidomide in the U.S., despite a small placebo-controlled trial in which eight of nine patients with AIDS-related wasting gained weight when treated with thalidomide, vs. only two of nine in the placebo group, a statistically significant difference.(1) Another placebo-controlled study reported statistically significant weight gain with thalidomide treatment in tuberculosis patients, many of whom also had HIV.(2) There have also been anecdotal reports of weight gain in persons with AIDS-related wasting.
AIDS buyers' clubs, after much thought and investigation, responded and obtained thalidomide for persons with wasting syndrome. (Thalidomide has long been used in Brazil and other countries -- including the U.S. -- in the treatment of leprosy.) The FDA was upset, and sent the clubs increasingly threatening demands that they stop supplying the drug. The buyers' clubs have made it clear that they are willing to do so -- but not until there is an FDA-approved program which is effectively supplying the drug to the people who desperately need it. The reason for the FDA's concern, of course, is that thalidomide can cause birth defects if taken by pregnant women.
About 35 years ago, before this was known, thalidomide caused thousands of deformities in Europe, where it was prescribed for morning sickness. In the U.S., this disaster was prevented because the FDA had fortunately not approved thalidomide due to other safety concerns. This U.S. disaster which was averted by the FDA became a proud, defining historical moment for the organization.
What is happening now is that the FDA is temporarily accepting persons with AIDS-related wasting into its small compassionate-use program for persons with aphthous ulcers. This will end when Celgene Corporation of Warren, New Jersey, the company which is developing thalidomide for treatment of wasting, is ready with a program for wider use of the drug. [Note: While thalidomide is being developed for wasting syndrome by Celgene, it is being developed for aphthous ulcers by another company, Andrulis Pharmaceutical Corporation.] All three parties gain from the apparent compromise, and all give something up.
The FDA has been most anxious to shut down unofficial access to thalidomide through the buyers' clubs; the compromise will probably accomplish that. But the FDA has also been reluctant to allow a "treatment IND" compassionate access program with cost recovery, until more data is available than it now has about thalidomide and wasting. (A controlled trial for wasting is now ongoing, but it has had serious problems recruiting volunteers, because of exclusion conditions, and because it is placebo controlled when there is a standard of care (Megace or Marinol); persons with wasting syndrome severe enough to qualify for the trial are unwilling to risk getting no treatment.)
Something had to be done to justify shutting down the buyers' club supply -- hence the pressure to speed up plans for a second Celgene randomized trial, to provide alternative access. But at the October 24 meeting, it became clear that the resulting trial would not produce the kind of efficacy information the FDA wanted in any case, so there was no need for it to be randomized. The company had to give up its hope for randomized data. But it can charge for the program, and will get safety information from it. The buyers' clubs are convinced that they have given better service to patients than the official program will --and at a much lower cost. They had to give this up, but they did achieve their central goal -- the creation of an official program to distribute the drug for persons with wasting syndrome.
Thalidomide for Aphthous Ulcers:
New NIAID Results
On October 31, as this issue went to press, the U.S. National Institute of Allergy and Infectious Diseases announced that thalidomide had worked well enough in treating severe mouth ulcers (oral aphthous ulcers) that a major ongoing government study (ACTG 251) was being changed to no longer require persons with that condition to take a chance of receiving a placebo. Instead, the trial will continue, in order to collect data on maintenance use of thalidomide for this purpose; but all current and new volunteers with mouth ulcers will get the active drug.
In the trial so far, the ulcers healed in 14 of 23 patients receiving thalidomide, but only one of 22 who received the placebo. Volunteers with aphthous ulcers of the esophagus will still be randomly assigned to thalidomide or placebo, however, because there has not yet been enough enrollment in the study to prove that the drug works for these ulcers as well.
This study is still open for enrollment in about 20 U.S. cities; it is seeking a total of 164 volunteers. For more information, call the AIDS Clinical Trials Information Service, 800/TRIALS-A.
This result is no surprise. The medical literature has been full of successful reports of thalidomide use in aphthous ulcer treatment for the last five years. Other AIDS-Related Uses: Kaposi's Sarcoma? Microsporidiosis? If anyone using thalidomide alsohas Kaposi's sarcoma (KS), we would like to hear if the drug seemed to have any effect on that disease. An animal study published last year found that oral thalidomide inhibited angiogenesis (the growth of new blood vessels), and concluded that the drug had promise as a possible treatment "of many diverse diseases dependent on angiogenesis."(3) (The abstract did not mention Kaposi's sarcoma specifically, and is not included on the AIDSLINE computer database.)
A small study (17 volunteers) in England, reported at the recent AIDS conference in Copenhagen, found improvement in diarrhea due to microsporidiosis after treatment with thalidomide, in patients who had failed to respond to previous treatment with albendazole.(4) This trial was organized after earlier research found that persons with AIDS-related microsporidiosis had abnormally high levels of TNF (tumor necrosis factor, which has many effects on the body) in their feces. Thalidomide reduces TNF levels. In addition, there is interest in thalidomide as a possible treatment for other illnesses which are not AIDS related, including lupus, and some cancers.
We are concerned that removal of thalidomide from the buyers' clubs will make it more difficult to explore new possible uses for the drug. Official clinical research is usually years behind the leading front-line scientists, physicians, and patients.
FDA Compassionate Access Program
The FDA program for compassionate access to thalidomide -- originally set up for persons with aphthous ulcers, then temporarily used for persons with AIDS-related wasting syndrome -- is still open for wasting syndrome. This program is free; but its use for wasting will be ended when the Celgene open-label safety protocol is ready.
For information about the FDA compassionate-access program, contact Matthew Tarofsky or Brenda Atkins, 301/443-9553.
Comment - Charging for Trials
The entire issue of charging patients for the costs of research -- research undertaken not for their benefit, but for the benefit of the pharmaceutical company which owns the rights to the drug -- needs much more attention. This problem must be seen in the larger context of pharmaceutical companies big and small shedding costs of developing their own proprietary drugs.
Insurance companies and government programs alike are usually adamant that they will not pay for the pharmaceutical companies' research -- and strong enough to avoid having to do so. The bills, then, go to desperate patients who have to pay out of their own pockets if they can pay at all, and give up the treatment they need if they cannot. The PWA Health Group was concerned that the earlier, randomized thalidomide trial-for-sale would set a new, dangerous precedent in this direction.
There is widespread fear that many pharmaceutical companies will happily make patients pay for research if they can get away with it -- a "Republican wet dream," one activist called it.
[It has long been noted that people are cheaper than monkeys for some clinical trials; they will be cheaper still if they have to pay their own way as guinea pigs.]
Already it has become a widespread practice to force volunteers to pay for laboratory tests required by research protocols. Note that charging for COMPASSIONATE ACCESS (including "treatment IND" and other programs set up primarily for treatment, not for research) is also an issue, but a different one than charging clinical-trial volunteers for DRUG RESEARCH AND DEVELOPMENT. Compassionate access is for the patient's benefit, not the pharmaceutical company's; it should be reimbursed as part of medical care.
The problem is that insurance companies and other third-party payers, public and private, have control of the rules, and have abused their power by extending their understandable refusal to pay for other companies' drug development to also refusing to pay for treatment on the grounds that it is "experimental" -- even when the clear purpose of the medication is treating the patient, not drug development.
These compassionate access programs provide some of the most important medical treatment, simply because they are seldom set up except in cases of desperate need. To single out this most urgent medical expense for refusal of coverage is unconscionable. This issue has been obscured because pharmaceutical companies have been expected to pay for compassionate access out of their research and development budgets; patients and payers alike did not see the bill.
It has been argued that it is inherently immoral to charge for a drug which has not been proven safe and effective. We believe this whole area needs more attention. Sometimes the drugs are not available at all unless companies can charge for them. And requiring that research funding cover these programs might slow development of new drugs. These problems would be greatly reduced if, when an unapproved drug is the best option for a patient's therapy, it could be reimbursed like any other medical care. (In addition, pharmaceutical companies need to continue to help patients obtain reimbursement for which they are qualified, and to set aside some proportion of the drug for an indigent program for patients who cannot be reimbursed.)
Research and medical costs which should legitimately be paid by others must not be dumped onto the individual patient, just because powerful institutions are fighting among themselves over who should pay. Patients, physicians, and the general public are in an excellent position to organize politically against this.
1. Reyes-Teran G, Sierra-Madero JG, Martinez del Cerro V. and others. Effects of thalidomide on wasting syndrome in patients with AIDS. A randomized, double-blind, placebo controlled clinical trial. International Conference on AIDS, Yokohama, August 7-12 1994 [abstract # 536B].
2. Tremontana JM, Utaipat U, Molloy A and others. Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis. MOLECULAR MEDICINE May 1995; volume 1, number 4, pages 384- 397.
3. D'Amato RJ, Loughnan MS, Flynn E, and Folkman J. Thalidomide is an inhibitor of angiogenesis. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA, April 26, 1994; volume 91, number 9, pages 4082-4085.
4. Sharpstone D, Rowbottom A, Francis N and others. A novel therapy for microsporidiosis. Fifth European Conference on Clinical Aspects and Treatment of HIV Infection, Copenhagen September 27-29, 1995 [abstract #92].